Initial Thrombotic Thrombocytopenic Purpura Research Articles

Mind and matter: The neurological complications of thrombotic thrombocytopenic purpura.

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.

Cost savings to hospital of rituximab use in severe autoimmune acquired thrombotic thrombocytopenic purpura

AbstractPatients with severe autoimmune thrombotic thrombocytopenic purpura (TTP) experience acute hematologic emergencies during disease flares and a lifelong threat for relapse. Rituximab, in addition to steroids and therapeutic plasma exchange (TPE), has been shown to mitigate relapse risk. A barrier to care in initiating rituximab in the inpatient setting has been the presumed excessive cost of medication to the hospital. Retrospectively reviewing TTP admissions from 2004 to 2018 at our academic center, we calculated the actual inpatient cost of care. We then calculated the theoretical cost to the hospital of initiating rituximab in the inpatient setting for both initial TTP and relapse TTP cohorts, with the hypothesis that preventing sufficient future TTP admissions offsets the cost of initiating rituximab in all patients with TTP. At a median follow-up of 55 months in the initial TTP cohort, rituximab use produced a projected cost savings of $905 906 and would have prevented 185 inpatient admission days and saved 137 TPE procedures. In the relapse TTP setting, rituximab use produced a projected cost savings of $425 736 and would have prevented 86 inpatient admission days and saved 64 TPE procedures. From a hospital cost standpoint, cost of rituximab should no longer be a barrier to initiating inpatient rituximab in both initial and relapse TTP settings.

Relapsing Thrombotic Thrombocytopenic Purpura: A Single Center Experience

Thrombotic thrombocytopenic purpura (TTP) is due to a severe deficiency of the von Willebrand factor (vWF) cleaving serine metalloprotease ADAMTS13 and is most commonly diagnosed in adults due to autoantibodies against ADAMTS13. Standard therapy includes plasma exchange (PEX) until platelet counts normalize plus concurrent high dose corticosteroids. In refractory cases, weekly pulse Rituximab for 4 doses is often added. Successful long-term management of relapsing patients beyond these treatments is unclear, in part because the mechanisms for relapsing TTP are unknown. Dysfunctional immunoregulatory systems likely play a role in relapsing disease. Several case series have described disease control following bortezomib therapy (Patriquin 2016). Other immunomodulators including complement pathway and tyrosine kinase inhibitors may prove to offer benefit. Further, supplementing PEX with N-acetylcysteine (Rottenstreich 2016) & Caplacizumab (anti-vWF humanized immunoglobulin) (Peyvandi 2016) has shown promising preliminary clinical results when used to treat an acute episode. Effects on relapse rates with these treatments have not been fully evaluated.Eight cases of relapsing TTP were identified at MedStar Georgetown University Hospital May 2004 to July 2016. Relapsing TTP was defined as recurrent episode(s) of thrombocytopenia, microangiopathic hemolysis, and confirmed ADAMTS13 activity levels <10% following remission from the initial TTP episode. Retrospective chart review was completed to evaluate demographic and clinicopathologic features, laboratories and treatment at relapse(s), and clinical outcomes.In our 8 patient cohort, 75% are female (6/8), 62.5% are African American (AA) (5/8), and the mean age at initial TTP diagnosis is 35.38 (range 16-67). The mean number of relapses is 3.38 (range 2-9) with a mean platelet nadir of 45,000/mcL. All patients remain alive. Two are ANA positive, 1 with known systemic lupus erythematosus (SLE) and 1 with suspected SLE. None are HIV positive, and none endorse a family history of TTP. Four identified infections as triggers for their TTP, 1 patient developed TTP during pregnancy and hormonal fertility treatments, and 3 had no identifiable triggers. All had an increased titer of ADAMTS13 inhibitor (Bethesda titer range 0.7 - >8) at the time of relapse(s). Normalization of ADAMTS13 activity was confirmed in most following treatment (n=6), with a mean ADAMTS13 activity level between relapses of 50.5% (range 32-88%). At the time of each relapse, all patients underwent daily PEX with fresh frozen plasma plus high dose corticosteroids for at least 5 days (range 5-21 days), with some requiring gradual PEX weaning over 1-4 weeks and steroid tapering over months based on lab parameters. Two relapsed quickly after PEX discontinuation, both in the setting of systemic illness (lupus flare, cholecystitis). Sequelae of TTP (neurologic, renal, hematologic anomalies) resolved with treatment. All patients received Rituximab therapy during the 1st or 2nd relapse. For the majority (87.5%, 7/8), this intervention did not lead to long-term remission, although 100% (2/2) who transitioned to prophylactic bolus Rituximab every 6 months post splenectomy achieved long-term disease control. It is difficult to distinguish whether remission resulted from maintenance Rituximab, the splenectomy, or a combination of the two. Patients who underwent splenectomy were vaccinated and have not had difficulty with infections or thrombosis.In conclusion, our cohort of patients with relapsing TTP all had documented ADAMTS13 inhibitors and acutely responded to daily PEX (most requiring PEX wean based on lab parameters) plus high dose corticosteroids. Although Rituximab therapy during initial relapse did not offer a high percentage of long-term remissions, the addition of prophylactic Rituximab every 6 months post splenectomy has achieved long-term control in 2 patients. In our cohort the majority are AA, suggesting genetic susceptibility. HLA/immune transcript levels and ribosomal gene signatures may correlate with TTP disease activity and risk for relapse (Edgar 2015), and could be used to identify high-risk patients in need of more intensive therapy. Given the complexity and severity of this disease, there is an ongoing need for evaluation of relapsing TTP and best strategies for long-term management. [Display omitted] DisclosuresKessler:Octapharma: Consultancy, Research Funding; Novo Nordisk: Consultancy, Research Funding; Grifols: Consultancy; Genentech: Consultancy, Research Funding; Biogen: Consultancy; Pfizer: Consultancy; Bayer: Consultancy, Research Funding; Baxalta: Consultancy, Research Funding; LFB: Other: Member of DSMB. Broome:True North Therapeutics: Honoraria; Alexion Pharmaceuricals: Honoraria.

No Major Differences in Outcomes Between the Initial and Relapse Episodes in Patients with Thrombotic Thrombocytopenic Purpura: The Experience from the Ohio State University Registry

Background:Thrombotic thrombocytopenic purpura (TTP) is characterized by consumptive thrombocytopenia and microangiopathic hemolytic anemia. At least a third of the patients with TTP will have one or more relapses throughout their life. There is very little data regarding the differences, if any, in clinical presentation and outcomes between the initial and subsequent TTP episodes. This information is relevant to understand if patients that present initially and those that present with a relapse can be seen as equal when being considered for clinical trials. Identifying the characteristics of patients that are prone to relapse will help guide the monitoring of patients after an acute episode of TTP to help to prevent relapse.Methods:Between March 2003 and June 2016 we collected clinical and laboratory data on all patients that presented to the Ohio State University with a diagnosis of acquired TTP (aTTP). The diagnostic criteria for aTTP included: thrombocytopenia, and a microangiopathic hemolytic anemia without an alternative explanation. The diagnosis was confirmed by the finding of severely deficient ADAMTS13 activity (<10%). Patients were consented to participate in our TTP registry and the information obtained included initial clinical presentation, platelets, LDH, kidney function, ADAMTS13 activity and inhibitor titer, number of plasma exchange (PEX) to achieve remission (defined as number of PEX needed to obtain a normal platelet count), and the outcome of the episode; clinical response (normal platelet count and LDH), exacerbation (recurrent TTP within 30 days of last PEX procedure), refractory (more than 30 PEX needed to obtain a clinical response), or death.Results:- All the patients enrolled were included in the study, except those with active cancer, leaving a total of 125 episodes from 57 patients.- 36 of the 57 patients had two or more TTP episodes (relapse rate 63.1%), with 21 of the 57 patients having 3 or more episodes. The time between episodes varied greatly, from 2 months to 8 years.- Of the 125 episodes, there were 42 initial and 83 relapses.- The initial group presented with central nervous system (CNS) symptoms more commonly than the relapse group. They also had significantly lower platelets and a higher LDH than the relapse group.- Regarding treatment, there was no significant difference in the number of PEX needed to achieve remission between the 2 groups. However, there was a significant number of patients in the initial group that needed more than 5 PEX to achieve remission, compared to the relapse group (p<0.0001)- There were no significant differences in the main clinical outcomes between the initial and relapse groups in rates of clinical response (p=0.267), exacerbation (p=0.483), refractory (p=0.075) or death (p=0.066)Conclusions:In their first episode of TTP, patients may present more ill than those patients having relapses (with more CNS symptoms, lower platelets and higher LDH), and may also require more PEX sessions to achieve remission. However, these findings do not change outcomes, and patients in their initial presentation and relapses can be seen as equal in terms of clinical response, exacerbation, refractory disease, and mortality rates. The high relapse rate seen in our registry may be due to the prolonged follow up (13 years) which is more than other series reported. Patients may have a relapse even after several years of being stable. [Display omitted] [Display omitted] DisclosuresNo relevant conflicts of interest to declare.

Seasonal distribution of severe ADAMTS13 deficient idiopathic thrombotic thrombocytopenic purpura

Idiopathic thrombotic thrombocytopenic purpura (TTP) is a rare yet potentially fatal thrombotic microangiopathy. Severe deficiency of ADAMTS13 activity via autoantibody formation has been associated with idiopathic TTP; however, specific triggers are poorly defined. Previous studies have reported seasonal associations of TTP, with warm-weather seasons appearing to have the strongest predilection. We characterized the seasonal distribution of severe ADAMTS13 deficient idiopathic TTP at our multi-hospital institution. Apheresis records from 2005-2012 were queried for patients with a clinical diagnosis of TTP, accompanying pre-plasmapheresis ADAMTS13 activity <10%, and no other explanations for thrombotic microangiopathy. Date of admission and ADAMTS13 activity were collected. Both initial episodes and relapses in patients whose initial episodes occurred since 2005 were included in the analysis. Goodness-of-fit chi-square analysis was performed and statistical significance was defined as p<0.05. Of 237 consecutive new patients with a suspected clinical diagnosis of TTP, 73 patients met inclusion criteria and had a total of 110 unique presentations for either initial TTP episodes or TTP relapses. Sixteen patients had 37 relapses of their idiopathic TTP (range 1-7). No statistically significant seasonal or monthly associations were identified with either initial or any TTP episodes. A seasonal association of severe ADAMTS13 deficient idiopathic TTP was not observed. Unknown variables may explain previous observations of seasonal associations of idiopathic TTP in other regions of the United States. Thus, individual institutions should characterize their own seasonal distributions of idiopathic TTP as part of the exploration of possible disease triggers in their respective areas.

Pearls &amp; Oy-sters: Acute ischemic stroke caused by atypical thrombotic thrombocytopenic purpura

Thrombotic thrombocytopenic purpura (TTP) is an episodic microangiopathic coagulopathy characterized by profound thrombocytopenia and hemolytic anemia. Neurovascular complications, including stroke and TIA, occur commonly upon initial TTP presentation, and the underlying etiology of such neurologic manifestations is usually hinted by the concomitant hematologic abnormalities.

Unexpected frequency of Upshaw-Schulman syndrome in pregnancy-onset thrombotic thrombocytopenic purpura

AbstractPregnancy may be complicated by a rare but life-threatening disease called thrombotic thrombocytopenic purpura (TTP). Most cases of TTP are due to an acquired autoimmune or hereditary (Upshaw-Schulman syndrome [USS]) severe deficiency of a disintegrin and metalloprotease with thrombospondin type 1 repeats, member 13 (ADAMTS13). In the present study, we performed a cross-sectional analysis of the national registry of the French Reference Center for Thrombotic Microangiopathies from 2000-2010 to identify all women who were pregnant at their initial TTP presentation. Among 592 adulthood-onset TTP patients with a severe ADAMTS13 deficiency, 42 patients with a pregnancy-onset TTP were included. Surprisingly, the proportion of USS patients (n = 10 of 42 patients [24%]; confidence interval, 13%-39%) with pregnancy-onset TTP was much higher than that in adulthood-onset TTP in general (less than 5%) and was mostly related to a cluster of ADAMTS13 variants. In the present study, subsequent pregnancies in USS patients not given prophylaxis were associated with very high TTP relapse and abortion rates, whereas prophylactic plasmatherapy was beneficial for both the mother and the baby. Pregnancy-onset TTP defines a specific subgroup of patients with a strong genetic background. This study was registered at www.clinicaltrials.gov as number NCT00426686 and at the Health Authority, French Ministry of Health, as number P051064.

Stroke in a young patient treated by alteplase heralding an acquired thrombotic thrombocytopenic purpura

Thrombotic thrombocytopenic purpura (TTP) is a life-threatening multisystem disorder characterized by thrombocytopenia and fluctuating neurological symptoms due to microinfarcts. In rare cases, large cerebral arteries can be occluded. We report on a 30-year-old woman with a first-ever acute stroke related to a right proximal MCA M1 occlusion. Platelet count was normal at admission and progressively decreased 6 days after intravenous thrombolysis with the occurrence of a hemolytic anemia with schistocytes. Most biological anomalies reversed after plasma exchange. No hemorrhagic complication occurred. Diagnosis of initial TTP was confirmed by low ADAMTS13 activity and positivity of anti-ADAMTS13 antibody. This observation highlights the fact that even if platelet count and hemoglobin rate are normal in the beginning, an acute ischemic stroke in a young patient can be related to TTP. Faced with subsequent thrombopenia, practitioners should be aware of acquired TTP, and, thus, schistocytes, haptoglobin, and LDH assays should be performed. Early diagnosis is paramount to start the life-saving plasma exchanges.

Identification of Trigger Factors Initiating an Acute TTP Episode in 68 Patients.

Recent research efforts have provided significant insight into the pathogenesis of thrombotic thrombocytopenic purpura (TTP). However, the low incidence of the disease hampers the identification of trigger factors initiating an acute TTP episode. In the present work data from 68 TTP patients were analyzed. The patients were asked by a questionnaire to provide data concerning age, gender, medical history, underlying and concomitant diseases and potential triggers. Additional laboratory and clinical data from onset of disease and remission phase were obtained by a second questionnaire completed by the physicians. Our study showed that long term abuse of nicotine is a predisposing factor with an OR of 3.19. The OR for obesity and development of TTP was 2.01. The influence of nicotine abuse has not yet been described whereas the association between obesity and development of TTP is already known. The intake of oral contraceptives (13 of 46 women/28%) of Tamoxifen, of Fluvastatin, of Ticlopidine and of Quinine was identified to be potential triggers. 55% (34 patients) of the patients reported infections and inflammations as triggers (mostly influenza (n=16) and gastroenteritis (n=14)). The relation of female and male patients was 3:1. The mean age, in which the initial TTP episode occurred, was significantly lower in female patients compared with the male patients (33.8 versus 43.8 years). Severe ADAMTS-13 deficiency was found in 91% in all investigated episodes of the patients. Inhibitory activity was associated with severe ADAMTS-13 deficiency in 81% of the cases. The comparison of patients during remission with and without relapses of TTP revealed a significant lower ADAMTS-13 activity in patients with relapsing TTP compared to patients without a relapse of TTP. This result suggests that ADAMTS-13 activity has prognostic value with respect to the occurrence of relapse.

Unraveling the immunologic response in thrombotic thrombocytopenic purpura.

Unraveling the immunologic response in thrombotic thrombocytopenic purpura.

Long-Term Follow-Up of 21 Patients with Thrombotic Thrombocytopenic Purpura (TTP) and Severe ADAMTS13 Deficiency: Demonstration of Persistent ADAMTS13 Deficiency and Neurocognitive Abnormalities.

Many patients who have recovered from TTP report cognitive abnormalities, often described as difficulty with attention, comprehension, and memory. These abnormalities have never been objectively documented. Also there have been reports of patients with continued abnormal ADAMTS13 activity following complete hematologic recovery; the frequency, duration, and clinical importance of persistent ADAMTS13 deficiency has not been described in a cohort of consecutive patients with long-term follow-up. To evaluate these unresolved issues, we measured neurocognitive function, ADAMTS13 activity, platelet count, and hematocrit (hct) in patients from the Oklahoma TTP-HUS Registry. The Registry has measured ADAMTS13 activity on 172/193 (89%) consecutive patients treated with plasma exchange for their initial episode of clinically diagnosed TTP-HUS from 11/13/1995 to 4/30/2003. 4/30/2003 was selected to assess patients with at least 1 year of follow-up after their initial episode. 29/172 (17%) patients with apparently acquired TTP had ADAMTS13 activity <10% at the onset of their initial episode; 22 patients survived. Although severe ADAMTS13 deficiency characteristic of TTP is usually defined as <5%, our 6 surviving patients with initial ADAMTS13 activity of 5–9% all had ADAMTS13 inhibitors; 2 have relapsed and had ADAMTS13 activity of <5% at the time of their 2nd episode. 21/22 patients, who have had follow-up of 0.25–8.25 years from their most recent episode, were evaluated. 9/21 (43%) patients have had between 1–4 relapses. None of the patients had symptoms or signs of TTP at the time of this assessment. The Rey Auditory-Verbal Learning Test (RAVLT) assesses new learning and recent memory. For new learning 11 (52%) patients and for recent memory 7 (33%) patients were below the 16th percentile for age/gender specific norms (p<0.01 and p=0.03 respectively). The Digit Span (DS) score, which assesses attention and concentration, was below the 25th percentile in 8 (38%) patients (p=0.17). 11/20 (55%) had moderate-severe depression symptoms documented by the Beck Depression Inventory-Second Edition (BDI–II) (8 patients) or by prescribed medication for depression (3 patients). ADAMTS13 activity was abnormal (<50%) in 11/21 patients (52%); 2 patients, who were 4.0 and 8.25 years from their most recent episode, had activity <3% with inhibitors; in the other 9 abnormal patients ADAMTS13 activity was 14–50% (median 35%). 19 patients were not thrombocytopenic (platelet counts 174–659, median 286). 1 patient (ADAMTS13 > 100%) with a platelet count of 105 had developed systemic lupus erythematosus after his initial TTP episode; 1 patient (ADAMTS13=50%) with a platelet count of 134 has had intermittent, mild thrombocytopenia since her initial episode 7 years ago. Five patients had mild anemia (hct 32–40%). Relapses, cognitive function, symptoms of depression, platelet count, and hct were not significantly different between patients with normal or abnormal ADAMTS13 activity. The neurocognitive abnormalities documented here may be related to the initial diffuse thrombotic disease. Depression may contribute to these abnormalities. Persistent abnormal ADAMTS13 activity many years after apparent recovery is common but of uncertain clinical importance since ADAMTS13 levels were not associated with clinical outcomes.

Proteolytic cleavage of von Willebrand factor by ADAMTS‐13 prevents uninvited clumping of blood platelets

Proteolytic cleavage of von Willebrand factor by ADAMTS‐13 prevents uninvited clumping of blood platelets

Recovery and Half-Life of von Willebrand Factor-Cleaving Protease after Plasma Therapy in Patients with Thrombotic Thrombocytopenic Purpura

Plasma exchange using fresh-frozen plasma (FFP) for replacement was given to two brothers during a relapse of thrombotic thrombocytopenic purpura (TTP). A constitutional deficiency of von Willebrand factor(vWF)-cleaving protease had been previously established in both patients. No inhibitor of vWF-cleaving protease was present in patients' plasmas. They received plasma exchange for four and three consecutive days, respectively. In both patients, the activity of vWF-cleaving protease after the first plasmapheresis session was evaluated and was found to be virtually identical to anticipated activity calculated from predicted patient plasma volume and volume of exchanged plasma. Pathologic platelet counts and lactate dehydrogenase levels were normalized in both patients within 4-6 days. The biologic half-life of vWF-cleaving protease was determined in these patients following the last plasma exchange. The respective half-lives of 3.3 and 2.1 days represent the lowest known clearance rates of proteases in circulating human plasma. Another patient with relapsing TTP was treated with plasma exchange and/or plasma infusion for 10 consecutive days during the first relapse, 221-231 days after the initial TTP event. Pharmacokinetic studies of vWF-cleaving protease were performed after plasma exchange on day 221 and after plasma infusion on day 231. High level of an IgG in patient plasma, capable of completely inhibiting protease activity in an equal volume of normal plasma, had been established prior to first plasmapheresis. There was no measurable protease activity at any time during plasma therapy. Following plasma exchange, the level of the inhibitor was transiently slightly depressed. After 10 days of plasma therapy, the concentration of the inhibitor in patient plasma was increased about 5-fold. We suggest that, in contrast to protease deficient patients without circulating inhibitor, complementary therapy including immunosuppressive treatment, vincristine and/or splenectomy is indicated in patients with acquired inhibitors of vWF-cleaving protease. Testing for vWF-cleaving protease inhibitor may be useful in predicting the response to plasma exchange in patients with TTP.

Acquired Deficiency of von Willebrand Factor-Cleaving Protease in a Patient With Thrombotic Thrombocytopenic Purpura

Plasma of patients with thrombotic thrombocytopenic purpura (TTP) has been shown to contain unusually large von Willebrand factor (vWF) multimers that may cause platelet agglutination in vivo. Fresh frozen plasma infusions and plasma exchange represent the most efficient therapy of acute TTP. A specific protease responsible for cleavage of vWF multimers has been recently isolated from normal human plasma and was found to be deficient in four patients with chronic relapsing TTP. We examined the activity of the vWF-cleaving protease in plasma samples collected over a period of 400 days from a further patient with recurrent episodes of TTP who was treated by plasma exchange, plasma infusion, vincristine, corticosteroid therapy, and splenectomy. Complete deficiency of the vWF-cleaving protease was established during the first episode of TTP. The ensuing normalization of the platelet count was associated with the appearance of the protease activity. Three months after remission from the initial TTP event, the vWF-cleaving protease again disappeared and the platelet count gradually decreased. Relapses of severe thrombocytopenia occurred 7 and 11 months after the first acute episode of TTP. Deficient protease activity was associated with the presence in the patient plasma of an inhibitor that was found to be an IgG. Plasma exchange/infusion was followed by a temporary increase in the antibody titer, whereas treatment with vincristine led to a recovery of the platelet count without affecting the inhibitor concentration. Splenectomy and corticosteroid treatment resulted in disappearance of the autoantibody and normalization of the protease activity and of the platelet count. Our data suggest that the thrombocytopenia in this patient with TTP was associated with a lack of the vWF-cleaving protease activity depleted by an autoimmune mechanism. This case, together with our previously reported patients, leads us to conclude that acquired as well as constitutional deficiency of the vWF-cleaving protease may predispose to TTP.

Thrombotic thrombocytopenic purpura: The israeli experience

Since 1985, 13 patients with thrombotic thrombocytopenic purpura (TTP) have been treated at the Hadassah Hospital. 1 patient died during the acute episode and eight had one or more relapses. Using a scoring system, developed in a previous report ( Am J Med 1987; 83:437) to assess the severity of each episode, we found that 9 patients presented with severe TTP (score of 5–7) and four had milder symptoms (score 2–4). As reported previously, relapses were usually manifested by a milder clinical course, however 1 patient died during a relapse. The treatment for the initial TTP episode and the relapses consisted of steroids, platelet inhibitor drugs, vincristine and frequent plasma transfusions or exchanges and varied according to the severity of the disease. 4 patients underwent splenectomy. Two who failed to respond to conventional therapy underwent splenectomy and recovered following additional plasma therapy. The other two underwent splenectomy while in remission, in order to prevent frequent relapses. A significant favourable change in the course of their disease was observed.