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Acute thrombocytopenic purpura (TTP) may present at any stage of pregnancy and the puerperium. Without prompt diagnosis and therapy, serious maternal and fetal outcomes may result. ADAMTS13 replacement via plasma exchange and immunosuppression are the mainstay of treatment. There may be a role, however, for newer therapies, including caplacizumab and recombinant ADAMTS13. Differentiation of immune TTP and congenital TTP is vital, particularly to guide the management of subsequent pregnancies., (© 2024 British Society for Haematology and John Wiley & Sons Ltd.)

A young adult African American female presented with normocytic microangiopathic haemolytic anaemia, elevated lactate dehydrogenase and thrombocytopenia. The patient responded to therapeutic plasma exchanges (TPE) for presumed thrombotic microangiopathy caused by thrombotic thrombocytopenic purpura (TTP). After relapsing, the patient was found to have pancytopenia, megaloblastic bone marrow and low vitamin B12 consistent with pernicious anaemia, which improved with intramuscular B12 and discontinuation of TPE. B12-deficient macrocytosis was not seen at presentation due to concomitant alpha-thalassaemia. Initial clinical/laboratory improvement is attributed to B12 present in TPE plasma. B12 deficiency can mimic TTP. Vigilance is needed regarding atypical presentations of pernicious anaemia., (© 2024 The Author(s). British Journal of Haematology published by British Society for Haematology and John Wiley & Sons Ltd.)

Immune-mediated thrombotic thrombocytopenic purpura (iTTP) is a rare and life-threatening disease that may result from drug exposure. We report a case of iTTP occurring in a 39-year-old patient, 45 months following introduction of the anti-CD52 lymphoid cell depleting monoclonal antibody alemtuzumab, to treat a relapsing-remitting multiple sclerosis. Treatment consisted in plasma exchange, corticosteroids and caplacizumab, allowing clinical remission 3 months after the diagnosis, attested by the absence of thrombocytopenia and recovery of ADAMTS-13 activity. As other autoimmune disorders, iTTP may occur following alemtuzumab. This diagnosis should be suspected in patients with features of thrombotic microangiopathy following this treatment., (© 2023 The Authors. British Journal of Haematology published by British Society for Haematology and John Wiley & Sons Ltd.)

Immune-mediated thrombotic thrombocytopenic purpura (iTTP) is a rare condition caused by severe ADAMTS13 deficiency, leading to platelet aggregation and thrombosis. Despite treatment, patients are prone to cognitive impairment and depression. We investigated brain changes in iTTP patients during remission using advanced magnetic resonance imaging (MRI) techniques, correlating these changes with mood and neurocognitive tests. Twenty iTTP patients in remission (30 days post-haematological remission) were compared with six healthy controls. MRI scans, including standard and specialized sequences, were conducted to assess white matter health. Increased T1 relaxation times were found in the cingulate cortex (p < 0.05), and elevated T2 relaxation times were observed in the cingulate cortex, frontal, parietal and temporal lobes (p < 0.05). Pathological changes in these areas are correlated with impaired cognitive and depressive scores in concentration, short-term memory and verbal memory. This study highlights persistent white matter damage in iTTP patients, potentially contributing to depression and cognitive impairment. Key regions affected include the frontal lobe and cingulate cortex. These findings have significant implications for the acute and long-term management of iTTP, suggesting a need for re-evaluation of treatment approaches during both active phases and remission. Further research is warranted to enhance our understanding of these complexities., (© 2023 The Authors. British Journal of Haematology published by British Society for Haematology and John Wiley & Sons Ltd.)

Immune thrombotic thrombocytopenic purpura (iTTP) is an ultra-rare disease that seldom occurs in the elderly. Few reports have studied the clinical course of iTTP in older patients. In this study, we have analysed the clinical characteristics at presentation and response to therapy in a series of 44 patients with iTTP ≥60 years at diagnosis from the Spanish TTP Registry and compared them with 209 patients with <60 years at diagnosis from the same Registry. Similar symptoms and laboratory results were described in both groups, except for a higher incidence of renal dysfunction among older patients (23% vs. 43.1%; p = 0.008). Front-line treatment in patients ≥60 years was like that administered in younger patients. Also, no evidence of a difference in clinical response and overall survival was seen in both groups. Of note, 14 and 25 patients ≥60 years received treatment with caplacizumab and rituximab, respectively, showing a favourable safety and efficacy profile, like that observed in patients <60 years., (© 2023 British Society for Haematology and John Wiley & Sons Ltd.)

Real-world registry studies of older patients with iTTP highlight diagnostic difficulties in comparison to patients less than 60 years of age with greater risk of renal injury, atypical neurological features and less profound cytopenia, which can result in diagnostic delays. However, there is no clear signal of significantly increased toxicity from full active treatment. Commentary on: Gómez-Seguí et al. Immune thrombotic thrombocytopenic purpura in older patients: results from the Spanish TTP Registry (REPTT). Br J Haematol 2023;203:860-871., (© 2023 British Society for Haematology and John Wiley & Sons Ltd.)

The objective of this guideline is to provide healthcare professionals with clear, up-to-date and practical guidance on the management of thrombotic thrombocytopenic purpura (TTP) and related thrombotic microangiopathies (TMAs), including complement-mediated haemolytic uraemic syndrome (CM HUS); these are defined by thrombocytopenia, microangiopathic haemolytic anaemia (MAHA) and small vessel thrombosis. Within England, all TTP cases should be managed within designated regional centres as per NHSE commissioning for highly specialised services., (© 2023 British Society for Haematology and John Wiley & Sons Ltd.)

Thrombotic thrombocytopenic purpura (TTP) is a rare and potentially fatal condition, with >90% mortality if untreated; deficiency of ADAMTS13 leads to widespread microvascular thromboses and organ injury particularly affecting organs with high shear stress, including the brain. The acute neurological complications have historically been those most feared by clinicians and synonymous with a poor prognosis. TTP, however, is no longer perceived as two extremes of acute presentation and remission, rather once diagnosed a chronic condition with the potential for a long-term symptom burden. Optimal neuroimaging timing and modality lacks consensus and as we learn more about the changes seen during the acute and chronic stages of TTP, there is scope for neuroimaging to play a greater role in guiding management and the secondary prevention of vascular disease. Reduced ADAMTS13 activity levels have been associated with increased thrombotic risk and novel therapies including caplacizumab and recombinant ADAMTS13 may offer a neuroprotective role. Given the increasing evidence of the neurocognitive and psychological disease in TTP, the importance of screening and timely intervention should not be underestimated. As more patients are surviving their initial TTP presentation, it is crucial for us to develop a greater understanding of the longer-term morbidity affecting these patients., (© 2022 British Society for Haematology and John Wiley & Sons Ltd.)

The 100th anniversary of the first description of Thrombotic Thrombocytopenic Purpura (TTP) as a disease by Dr. Eli Moschcowitz approaches. For many decades, TTP remained mostly a mysterious fatal condition, where diagnosis was often post-mortem. Initially a pentad of symptoms was identified, a pattern that later revealed to be fallible. Sporadic observations led to empiric interventions that allowed for the first impactful breakthrough in TTP treatment, almost 70 years after its first description: the introduction of plasma exchange and infusions as treatments. The main body of knowledge within the field was gathered in the latest three decades: patient registries were set and proved crucial for advancements; the general mechanisms of disease have been described; the diagnosis was refined; new treatments and biomarkers with improvements on prognosis and management were introduced. Further changes and improvements are expected in the upcoming decades. In this review, we provide a brief historic overview of TTP, as an illustrative example of the success of translational medicine enabling to rapidly shift from a management largely based on empiricism to targeted therapies and personalized medicine, for the benefit of patients. Current management options and present and future perspectives in this still evolving field are summarized., (© 2022 The Authors. British Journal of Haematology published by British Society for Haematology and John Wiley & Sons Ltd.)

Congenital thrombotic thrombocytopenic purpura (cTTP), known as Upshaw-Schulman syndrome, is an ultrarare thrombotic disorder caused by ADAMTS13 gene mutations; however, its long-term outcomes have not been widely studied. A questionnaire survey was administered to physicians of patients in the Japanese cTTP registry to characterise these outcomes. We analysed 55 patients in remission, with 41 cases receiving prophylactic fresh frozen plasma (FFP; median dosage: 13·2 ml/kg per month) and 14 receiving on-demand FFP. Patients receiving prophylactic FFP were considered as having a more severe form of the disease and had lower platelet counts and higher serum creatinine levels than those receiving on-demand FFP (median 138 × 10 9 /l vs. 243 × 10 9 /l, P = 0·003 and 0·71 mg/dl vs 0·58 mg/dl, P = 0·009, respectively). Patients who received prophylactic FFP more commonly developed organ damage, including renal impairment, cerebral infarctions, and cardiac hypofunction, than those who did not. Adverse FFP-related events were seen in 78% of the prophylactic FFP group, with allergic reactions being most common. Since current protocols for FFP administration to the prophylactic FFP group in Japan may be insufficient for preventing cumulative organ damage, a higher dosage of ADAMTS13 supply using recombinant ADAMTS13 agent is needed in these patients., (© 2021 British Society for Haematology and John Wiley & Sons Ltd.)

The PLASMIC score is a recently described clinical scoring algorithm that rapidly assesses the probability of severe ADAMTS13 (a disintegrin and metalloproteinase with a thrombospondin type 1 motif, member 13) deficiency among patients presenting with microangiopathic haemolytic anaemia. Using a large multi-institutional cohort, we explored whether an approach utilizing the PLASMIC score to risk-stratify patients with suspected immune thrombotic thrombocytopenic purpura (iTTP) could lead to significant cost savings. Our consortium consists of institutions with an unrestricted approach to ADAMTS13 testing (Group A) and those that require pre-approval by the transfusion medicine service (Group B). Institutions in Group A tested more patients than those in Group B (P < 0·001) but did not identify more cases of iTTP (P = 0·29) or have lower iTTP-related mortality (P = 0·84). Decision tree cost analysis showed that applying a PLASMIC score-based strategy to screen patients for ADAMTS13 testing in Group A would have reduced costs by approximately 27% over the 12-year period of our study compared to the current approach. Savings were primarily driven by a reduction in unnecessary therapeutic plasma exchanges, but lower utilization of ADAMTS13 testing and subspecialty consultations also contributed. Our data indicate that using the PLASMIC score to guide ADAMTS13 testing and the management of patients with suspected iTTP could be associated with significant cost savings., (© 2019 British Society for Haematology and John Wiley & Sons Ltd.)

Acquired thrombotic thrombocytopenic purpura (TTP) is a rare, life-threatening condition caused by autoantibody-mediated inhibition of ADAMTS13 (a disintegrin and metalloproteinase with thrombospondin type-1 motif, 13). Therapeutic plasma exchange (TPE) improves survival, but disease may be refractory despite therapy. Management and treatment response of refractory TTP is variable, with rituximab and other immunosuppression often being used. Case reports have suggested a benefit of the proteasome inhibitor, bortezomib, possibly due to elimination of the autoreactive plasma cells producing anti-ADAMTS13 antibodies. We evaluated the effect of bortezomib in a series of primary refractory TTP patients unresponsive to intensive therapy. Bortezomib-treated patients were identified from consecutive cases managed at two UK referral centres. Demographic and clinical data were extracted from hospital records. ADAMTS13 activity was measured using a fluorescence resonance energy transfer VWF73 assay, and anti-ADAMTS13 IgG using enzyme-linked immunosorbent asssay. We identified six bortezomib-treated patients out of 51 consecutive cases of acute, acquired TTP. All patients received TPE, methylprednisolone and rituximab. Five of the six achieved complete remission with bortezomib, and one died of cardiac arrest due to underlying disease. No treatment-related adverse events were observed. Mean follow-up time after hospital discharge was 17 months (range: 3-33). Bortezomib appears effective in the treatment of a subgroup of cases with severe, refractory TTP. Prospective trials are required to further investigate this effect., (© 2016 John Wiley & Sons Ltd.)

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., (© 2015 John Wiley & Sons Ltd.)

Thrombotic thrombocytopenic purpura (TTP) is heralded by its demanding presentation and impending mortality. The complex and life-threatening characteristics of TTP justify the need for early referral and responsive management in centres with comprehensive multi-disciplinary resources. In an era where compromise of patient safety or experience is unsatisfactory, the provision of specialist-led, organized care for this patient group remains overdue. Patients and clinical teams continue to lack the knowledge, support and resources required to achieve consistently high levels of clinical care. This forms the rationale for development of TTP Specialist Centres. In this article we focus on what we believe to be the recognized and potential merits of a specialist service provision, highlighting individual components of a high level of integrated expertise. The challenges in managing the condition from acute diagnosis to long-term care are described alongside defining key standards that represent excellence in patient care. The emphasis will be on understanding how the evolution of TTP Specialist Centres diverges from an ad hoc approach to managing this vulnerable patient group and offers promise in the translation to improved patient outcomes., (© 2015 John Wiley & Sons Ltd.)

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., (© 2015 John Wiley & Sons Ltd.)

Thrombotic thrombocytopenic purpura (TTP) and atypical haemolytic uraemic syndrome (aHUS) are acute, rare life-threatening thrombotic microangiopathies that require rapid diagnosis and treatment. They are defined by microangiopathic haemolytic anaemia and thrombocytopenia, with renal involvement primarily in aHUS and neurological and cardiological sequelae in TTP. Prompt treatment for most cases of both conditions is with plasma exchange initially and monoclonal therapy (rituximab in TTP and eculizumab in aHUS) as the mainstay of therapy. Here we discuss the diagnosis and therapy for both disorders., (© 2014 The Authors. British Journal of Haematology Published by John Wiley & Sons Ltd.)

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., (© 2013 John Wiley & Sons Ltd.)

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., (© 2011 Blackwell Publishing Ltd.)

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.

Plasma exchange (PE) with plasma infusion is the treatment of choice for thrombotic thrombocytopenic purpura (TTP) but doubts remain as to whether all kinds of plasma are equally effective. A multicentric cohort study was conducted to compare methylene blue-photoinactivated plasma (MBPIP) with quarantine fresh frozen plasma (qFFP) in the treatment of TTP. One hundred and two episodes of idiopathic TTP were included; MBPIP was used in 63 and qFFP in 39. The treatment schedule consisted of daily PE and costicosteroids, and the main end-point was remission status on day 8. Patients treated with MBPIP required more PEs (median: 11 vs. 5, P = 0.002) and a larger volume of plasma (median: 485 ml/kg vs. 216 ml/kg, P = 0.007) to achieve a remission, and presented more recrudescences while on PE therapy (29 of 63 vs. 8 of 39, P = 0.02) than those receiving qFFP. After adjustment for possible confounding factors, the use of MBPIP was associated with a lower likelihood of remission on day 8 [Odds ratio (OR): 0.17; 95% confidence interval (CI): 0.06-0.47] and a higher risk of recrudescence while on treatment (OR: 4.2; 95% CI: 1.6-10.8). In conclusion, MBPIP is less effective than qFFP in the treatment of TTP.

Thrombotic thrombocytopenic purpura/Haemolytic uremic syndrome (TTP/HUS) is a thrombotic microangiopathy with a 6-month mortality rate of 16-29%. The present study described the clinical features, treatment regime and 6-month all-cause mortality rate of TTP/HUS patients at the London Health Sciences Centre (LHSC), Canada. Data for this retrospective cohort study were obtained from inpatient and outpatient records for all patients referred for plasma exchange therapy at LHSC, Canada between 1981 and 2006. Patients (n = 110) were categorized as: idiopathic primary (38%) or relapsed (16%), and secondary responsive (30%) or non-responsive (16%). Mortality data were available for all but three patients. The all-cause 6-month mortality rate was 19% overall and was 12% and 26% among idiopathic and secondary TTP/HUS patients, respectively. No mortality events occurred among the 17 idiopathic patients who relapsed. Relapsed patients had the least severe presenting characteristics, the fastest response time, and experienced significant improvement in the severity of clinical features between the first and final presentation. These findings suggest an excellent outcome for relapsed TTP/HUS patients. Patient education, surveillance, and aggressive plasma exchange therapy are hypothesized to improve the likelihood of survival: these hypotheses should be tested in a randomized controlled trial.

Thrombotic thrombocytopenic purpura (TTP) is an acute, rare, life-threatening disorder. This report presents the South East (SE) England registry for TTP, from April 2002 to December 2006, which included 176 patients and 236 acute episodes; 75% of patients were female and 25% were male, overall median age at presentation was 42 years. Mortality was 8.5%, most cases died before treatment was instigated. The main ethnic groups were Caucasian (64%) and Afro Caribbean (27%). Seventy-seven percent of cases were idiopathic, 5% were congenital and the remaining cases had a defined precipitant. Neurological features were the most prevalent, but cardiac involvement accounted for 42% of presenting features. The overall median number of plasma exchanges (PEXs) to remission was 15; between April 2002 and December 2003, the median number of PEXs was 19 and it was 12 between January 2004 and December 2006 (P < 0.0001). In the latter period, adjuvant therapies were reduced, but Rituximab was increased. ADAMTS 13 (a disintegrin and metalloproteinase with a thrombospondin type 1 motif, member 13) activity was <10% in 74% and 95% of these cases had positive IgG antibodies to ADAMTS 13. Renal impairment and delayed normalisation of platelet count were the main differences between idiopathic and secondary TTP.

Although diarrhoea-associated haemolytic uremic syndrome (HUS) in children is well described, the clinical features of bloody diarrhoea-associated thrombotic thrombocytopenic purpura (TTP)-HUS in adults are not documented. Twenty-one adults, 6.5% of the 322 adults in The Oklahoma TTP-HUS Registry, 1989-2006, have presented with bloody diarrhoea. There were no case clusters. Escherichia coli O157:H7 was identified in five patients, but many patients did not have appropriate studies. The annual incidence was 0.68/10(6), 10-fold less than the incidence of diarrhoea-associated HUS in children in Oklahoma. Two (13%) of 16 patients in whom ADAMTS13 (A Disintegrin And Metalloproteinase with a ThromboSpondin type 1 motif, member 13) was measured had <10% activity. Severe neurological abnormalities (67%) and renal failure (62%) were common; seven patients (33%) died; no survivors have relapsed. Compared to the 38 other Oklahoma Registry patients with ADAMTS13 <10%, frequency of severe neurological abnormalities and death was not different; frequency of renal failure was greater; frequency of relapse was less. Compared to 5999 children with sporadic diarrhoea-associated HUS in published reports, frequency of renal failure and relapse was not different; frequency of severe neurological abnormalities and death was greater (P < 0.05 for all differences). Awareness of the continuous occurrence of sporadic bloody diarrhoea-associated TTP-HUS in adults is important for prompt diagnosis and appropriate management.

We hypothesized that cyclosporin (CSA) as adjunct to plasma exchange (PE) improves the efficacy of PE in idiopathic thrombotic thrombocytopenic purpura (TTP) via suppression of the antibody inhibitor of ADAMTS13. Our preliminary findings with CSA and PE as the upfront treatment of TTP suggested that the addition of CSA to PE significantly decreased the exacerbation (disease recurrence within 30 d of the last PE) rates compared to a cohort that received corticosteroids and PE as their upfront therapy of TTP. We present an updated analysis with long-term follow-up of 18 patients with idiopathic TTP treated with concurrent CSA and PE with analysis of serial measurements of ADAMTS13 activity, antigen and inhibitor concentration in the context of clinical outcome data. Overall, 16/18 (89%) patients achieved remission, similar to historical remission rates in idiopathic TTP with PE with only one patient suffering an exacerbation. Clinical responses correlated with improvements in ADAMTS13 activity and suppression of the antibody inhibitor of ADAMTS13. These data suggest that the efficacy of CSA is at least in part related to its suppression of the antibody inhibitor of ADAMTS13 and a subsequent improvement in ADAMTS13 activity and antigen.

Thrombotic thrombocytopenic purpura (TTP) is a life-threatening disorder and plasma exchange (PEX) remains the primary treatment modality. Twenty-five patients with acute refractory/relapsing idiopathic TTP received rituximab in conjunction with PEX because of progressive clinical disease or deterioration in laboratory parameters, despite intensive standard therapy. In relapsing TTP, rituximab was started if antibody to ADAMTS-13 (a disintegrin and metalloproteinase with thrombospondin motif-13) was demonstrated during previous episodes. All 25 patients attained complete clinical and laboratory remission in a median of 11 d after initiating rituximab. In 21 cases, ADAMTS-13 activity was within the normal range following rituximab. Inhibitors were detected in 24/25 patients by mixing studies and/or immunoglobulin G (IgG) antibodies to ADAMTS-13 pre-rituximab. There was no evidence of inhibitors and/or IgG activity <10% in 23/25 patients following rituximab. In acute refractory cases, the median number of PEX pre-rituximab and following the first rituximab infusion was 13 and 9, respectively. There have been no infectious complications, despite low CD 19 levels and no relapses. In patients with acute refractory/relapsing idiopathic TTP, rituximab appears to be a safe, effective, targeted therapy with a significant reduction in the requirement for PEX.

We present the results of two consecutively performed cohort studies that evaluated the clinical effects of corticosteroids or cyclosporin as an adjunct to plasma exchange (PE) for the treatment of an acute episode of thrombotic thrombocytopenic purpura (TTP). In comparing 12 corticosteroid-treated patients with eight cyclosporin-treated patients, none of the cyclosporin-treated patients suffered an exacerbation or recurrence of TTP in the first 30 d after discontinuing PE compared with 6/10 (60%) of the corticosteroid-treated patients (P = 0.042). These data suggest that cyclosporin may have advantages over corticosteroids as an adjunct to PE therapy in the initial treatment of idiopathic TTP.

This report presents seven children with congenital thrombotic thrombocytopenic purpura (TTP). Six had a history of severe neonatal unconjugated hyperbilirubinaemia and thrombocytopenia. The seventh child had no neonatal problems but has suffered three episodes of acute TTP. The subsequent clinical course of the children varied. Five had a relapsing-remitting course and one had chronic microangiopathic haemolytic anaemia. The five oldest children initially received plasma infusions but, because of viral safety issues and easier administration, they now receive intermediate purity US-sourced plasma-derived factor VIII concentrate: BPL 8Y. Effective prophylaxis and treatment is possible in congenital TTP using BPL 8Y.

In order to assess the prognostic value of inhibitory anti-ADAMTS13 antibodies in thrombotic thrombocytopenic purpura (TTP), we performed a multicentre prospective study of 33 adult patients with idiopathic acquired TTP. Patients were treated with high-dose plasma infusion and therapeutic plasma exchange. Patients without (group 1, n = 12) and with (group 2, n = 21) detectable inhibitory anti-ADAMTS13 antibodies were compared for clinical presentation, treatment and outcome. Both groups were comparable for clinical presentation. All patients in group 1 achieved a sustained complete remission within a median of 7 d [95% confidence interval (CI), 4-18], which required a median plasma volume of 235 ml/kg (range, 131-1251). In group 2, 17 patients achieved a durable complete remission within a median of 23 d (95% CI, 11-32) (P = 0.001). Median plasma volume was 718 ml/kg (range, 219-3107) (P = 0.02). In group 2, there was a trend for more episodes of flare-up than in group 1 (13 vs. 3, respectively, P = 0.07). Four patients, all from group 2, died (P = not significant). The relapse rate was comparable between both groups. We suggest that TTP with detectable inhibitory anti-ADAMTS13 antibodies displays a worse prognosis, relative to a delayed platelet count recovery, a higher plasma volume requirement to achieve complete remission, and a trend for more frequent episodes of flare-up.

Despite the favourable response of thrombotic thrombocytopenic purpura/haemolytic uraemic syndrome (TTP/HUS) to plasma exchange, an early level of mortality persists. Non-response has been associated with a low frequency of exchange. The Rose index of TTP/HUS severity, occasionally used to predict the response of TTP/HUS to plasma exchange, remains unsatisfactory. The purpose of this study was to develop a new index predicting response of TTP/HUS to plasma exchange and to compare it with the Rose index. Retrospective analysis of 171 cases of TTP/HUS from 39 apheresis units across Canada between 1980 and 2001 was conducted. Logistic regression analysis was used to derive a model predicting 6-month mortality from presenting characteristics. The reduced model contained age >40 years, haemoglobin <9.0 g/dl and the presence of a fever at presentation. Gender, platelet count, creatinine and neurological signs were not part of the final model. This model predicted 13.4% of outcome variance. Predictive scores of 0, 2, 4 and 6 correlated with 6-month mortality rates of 12.5%, 14.0%, 31.3% and 61.5% respectively in our source population. This simple model may help identify those patients who would benefit from higher treatment intensity.

The therapeutic efficacy of plasma exchange (PE) in thrombotic thrombocytopenic purpura (TTP) is attributed to the restoration in ADAMTS-13 (a disintegrin and metalloproteinase with thrombospondin motif-13) activity by substitution of the enzyme and removal of ADAMTS-13-neutralizing autoantibodies. We explored this rationale by analysing ADAMTS-13 activity and corresponding inhibitor levels during PE-treatment in 27 episodes from 23 adults with TTP. All patients with an initial episode of TTP (n = 14) and nine of 11 patients with a relapse showed severe ADAMTS-13 deficiency. ADAMTS-13 inhibitors were detected in 81% of these patients. Twenty-one patients responded to PE-therapy and two patients died. For patients with severe ADAMTS-13 deficiency, 15 patients (71%) showed a PE-induced recovery in ADAMTS-13 activity and six patients (29%) had persistent severe ADAMTS-13 deficiency despite clinical response. Three patients with recurrent TTP demonstrated a permanent increase in inhibitor titre during therapy. Six patients (43%) with an initial episode of TTP displayed a transient increase in inhibitor titre during PE-therapy, which was associated with deterioration in clinical and haematological symptoms of TTP. Treatment with vincristine induced an immediate increase in platelet count and ADAMTS-13 activity in seven of eight patients. We conclude that ADAMTS-13 activity and inhibitor levels, as measured using current methodology, do not solely determine the clinical course of TTP.

A randomized prospective trial compared cryosupernatant plasma (CSP) to fresh frozen plasma (FFP) for treatment of thrombotic thrombocytopenic purpura (TTP). A total of 236 patients were required: 28 patients were treated with CSP and 24 with FFP within 30 months. There were no differences in survival at 1 month. By day 9, 17 of 26 patients with CSP and 18 of 24 with FFP had a platelet count >100 x 10(9)/l. At entry, von Willebrand factor (VWF) multimers were normal in all patients (range 1.1-3.95 IU/ml). ADAMTS-13 levels showed large variations ranging from 10% to 100% activity. At entry, no individual had <5% VWF cleaving protease. By day 9 (end of cycle), 89% (FFP) and 67% (CSP) had levels >50% of the controls. At 6 months some patients showed inhibitors to the enzyme in spite of adequate or normal platelet counts. The data from this study do not show an apparent advantage to the use of CSP in TTP. A large number of patients will be required to determine appropriate replacement therapy. We were not able to find a statistically significant relationship between the low level of protease activity at presentation of TTP and response.

We prospectively studied presentation biological differences and the response to therapy in patients with thrombotic thrombocytopenic purpura (TTP) associated with, or unrelated to human immunodeficiency virus (HIV) infection. TTP patients underwent standard evaluations and were treated with prednisone 1 mg/kg in addition to infusions of fresh frozen plasma (FFP; 30 ml/kg/d) until normalization of the platelet count. Unresponsive patients were referred for plasma exchange. Compared with HIV- TTP patients (n=23), in HIV+ subjects (n=21) microangiopathy was dominant among Black females, who had lower presentation Hb (median 5.8 g/dl; P=0.03), platelet count (13 x 10(9)/l; P=0.05) and a CD4 count of 0.096 x 10(9)/l. HIV+ individuals responded to FFP faster than HIV- patients and none of them required apheresis. Ten HIV- TTP patients required apheresis (P=0.03) and four died. Responses in the HIV+ and HIV- groups occurred after treatment with a median of 33 and 55 units (one unit=320 ml) of FFP (P=0.004) respectively. Response to this protocol was seen in 84% (95% response in HIV+ patients). Regression analysis showed that survival was associated with younger age (P=0.001), rapid platelet (P=0.001) and Hb (P=0.0009) recovery, and fewer FFP units to normal lactate dehydrogenase levels (P=0.006). We conclude that in HIV+ individuals, microangiopathy is highly responsive to plasma infusions. This observation is important particularly when apheresis is not available.

Venous thromboembolism (VTE) is not a feature of thrombotic thrombocytopenic purpura (TTP), but there has been a recent report of VTE in association with plasma exchange (PEX) treatment for TTP using the solvent detergent (SD) plasma, PLAS+SD. We reviewed the occurrence of VTE in 68 consecutive patients with TTP (25 men, 43 women). Eight documented VTE events [six deep venous thromboses (DVTs), three pulmonary emboli] were identified in seven patients (all female) during PEX therapy. All six DVTs were associated with central lines at the site of thrombosis. Other known precipitating factors included pregnancy, immobility, obesity and factor V Leiden heterozygosity. VTE occurred at a mean of 53 d following the first PEX. The European SD plasma, Octaplas was the last plasma to be used in PEX prior to the VTE in 7/8 events. This is the first report of VTE following Octaplas infusion. VTE is a multifactorial disease and, although several known precipitating factors were present in all patients in this study, the use of large volumes of SD plasma in PEX may be an additional risk factor. We recommend prevention of VTE with graduated elastic compression stockings (class I) at diagnosis and prophylactic low-molecular-weight heparin once the platelet count rises above 50 x 10(9)/l.

We have designed a simple test for the early diagnosis and treatment monitoring of thrombotic thrombocytopenic purpura (TTP). We examined plasma from 24 TTP patients and normal plasma using a cone and plate(let) analyser (CPA). Test plasma was mixed with citrated normal whole blood (group O) and subjected to flow at a shear rate of 1800/s. Mixing normal plasma (12.5, 25, 50 or 75 microl) with heterologous normal whole blood (final volume of 200 microl) resulted in a decrease of surface coverage (SC, maximally by 63%) and, to a lesser extent, of average size (AS, maximally by 37%) due to dilution of the blood sample. In contrast, mixing the same quantities of acute TTP plasma with normal blood yielded an increase in both SC (up to 125%) and AS (up to 130%). Increased SC and/or AS were detected in all 15 patients in acute phase and in three out of 14 patients in remission. Following repeated plasmapheresis, the enhanced platelet deposition in five patients with acute TTP returned to almost normal patterns. Mixing plasma from patients with other thrombocytopenic conditions in this way resulted in a decrease in both SC and AS, and did not differ from control subjects. In conclusion, the CPA is a simple and specific laboratory test that can be used for the diagnosis and monitoring of plasma exchange therapy in TTP.

Thrombotic thrombocytopenic purpura (TTP) is a rare but severe disorder characterized by microangiopathic haemolytic anaemia, consumptive thrombocytopenia, neurological involvement and formation of platelet thrombi in the small vessels. The aetiopathology of TTP and the mechanism behind the beneficial effect of plasma exchange with plasma infusion have not yet been fully elucidated. We have studied the effect of plasma from four patients with TTP on human blood phagocyte activation, as measured by reactive oxygen species (ROS) production and CD11b expression. TTP plasma obtained in the acute phase of the disease induced ROS production by human monocytes and enhanced CD11b expression on neutrophils. This activation effect remained in the cryosupernatant but not in the cryoprecipitate made from TTP plasma, and disappeared when a complete response was achieved by plasma exchange. These findings suggest that activated blood phagocytes may be involved in the pathophysiology of TTP.

There is increasing evidence that congenital thrombotic thrombocytopenic purpura (TTP) is caused by an absolute deficiency of von Willebrand factor-cleaving protease. The recent identification of this protease and the development of assays for its detection have enabled its quantification in a number of plasma products, including some commercial intermediate-purity plasma-derived factor VIII preparations. We report the successful, weekly prophylactic use of a commercial intermediate-purity plasma-derived factor VIII concentrate in the treatment of a 14-year-old girl with severe congenital TTP who had previously required transfusions of fresh-frozen plasma every 2 weeks from the age of 4 months.

Twenty patients with thrombotic thrombocytopenic purpura (TTP) underwent plasma exchange using either standard fresh-frozen plasma (Group A, n = 13) or methylene blue-treated plasma (Group B, n = 7). Both groups presented similar characteristics except that bilirubin values were higher in Group A (P < 0.05). The complete remission rate was higher in Group A than B (69% versus 57%). The mean number of procedures was higher in Group B (21 +/- 7 versus 11 +/- 3, P < 0.01) and the mean duration of hospitalization was also longer (37 +/- 12 d versus 22 +/- 11 d; P < 0.01). Our study shows that the use of methylene blue-treated fresh-frozen plasma to treat TTP is associated with a higher number of plasma exchanges and greater transfusion requirements without improving clinical results.

In a formal study, we have identified increasing age, pretreatment renal impairment and diabetes mellitus as risk factors for the development of intravenous immunoglobulin-induced renal failure. Identification of these characteristics in potential recipients should alert clinicians to the associated increased risk of this serious complication.