Recurrence Of Thrombotic Thrombocytopenic Purpura Research Articles

Recurrence of Thrombotic Thrombocytopenic Purpura After COVID-19 Vaccination: Correspondence.

Recurrence of Thrombotic Thrombocytopenic Purpura After COVID-19 Vaccination: Correspondence.

Analysis of five children with acquired thrombotic thrombocytopenic purpura

Objective: To investigate the clinical characteristics, treatment and prognosis of children with acquired thrombotic thrombocytopenic purpura (TTP). Methods: The clinical manifestations, laboratory examination, treatment and prognosis of 5 children with acquired TTP hospitalized in Beijing Children's Hospital, Capital Medical University from January 2016 to July 2019 were analyzed retrospectively. Results: There were 5 children with acquired TTP including 2 males and 3 females, with the onset age of 8.9(0.8-14.5) years, while 11 children with TTP in the same period. Thrombocytopenia and microangiopathic hemolytic anemia were found in all 5 patients. Only one patient had typical pentalogy of TTP, 3 patients had nervous system symptoms and 3 patients had fever, while renal impairment was relatively rare (1 case). Laboratory examination showed severe thrombocytopenia (7(4-14) ×109/L) and low level of hemoglobin (70(58-100)g/L) in all 5 children. Blood biochemical examination showed that total bilirubin (mainly indirect bilirubin) increased in 3 patients, lactate dehydrogenase increased in 5 patients, and urea nitrogen increased in 1 patient. Bone marrow smear showed megakaryocyte did not decrease. Plasma ADAMTS13 activity was 0 in all 5 patients while ADAMTS13 inhibitor was positive in 4 patients and negative in 1 patient. All 5 children received glucocorticoid therapy, rituximab was added in the early stage of the disease, and 3 children received plasma exchange. The time of platelet recovery to normal was 19 (9-29) days. One child had TTP recurrence after 9 months of treatment. The condition was stable after being treated with glucocorticoid and rituximab again. This case was finally diagnosed as systemic lupus erythematosus after more than 3 years followed up. By December 1, 2020, the follow-up time was 24(16-57) months.The clinical symptoms of all patients disappeared and the platelet level was stable at 159(125-269) ×109/L. Conclusions: Childhood acquired TTP is relatively rare, which can occur in all age groups. The clinical manifestations are mainly thrombocytopenia and microangiopathic hemolytic anemia, the plasma ADAMTS 13 activity and inhibitor test are helpful for the diagnosis of acquired TTP. Plasma exchange and rituximab are effective treatment. This disease requires long-term follow-up.

Thrombotic Thrombocytopenic Purpura and Atypical Hemolytic Uremic Syndrome in Pregnancy: A Single Center Retrospective Review

Introduction: Thrombotic Thrombocytopenic Purpura (TTP) is a rare, life-threatening disorder characterized by microangiopathic hemolytic anemia (MAHA), thrombocytopenia and is often associated with renal failure and neurologic manifestations. There are congenital and acquired forms of TTP both diagnosed by severe deficiency in ADAMTS13 a von Willebrand factor cleaving protease. Atypical Hemolytic Uremic Syndrome (aHUS), is also a rare disease with MAHA, thrombocytopenia, and acute kidney injury not related with Escherichia coli 0157:H7 infections and is caused by unregulated activation of the alternate complement pathway. Although established that pregnancy may predispose to TTP and aHUS, little is understood regarding outcomes and effect on subsequent pregnancies. We report clinical outcomes of patients with TTP and aHUS during pregnancy at University of Florida (UFH). Methods: Pregnant patients between age 18- 45 admitted to UFH between January 2010 - December 2016 with clinical diagnosis of TMA (TTP, atypical HUS, HUS, drug induced HUS,) were identified by ICD 9/10 codes (ICD 10- CM - M31.1, ICD-9-CM 446, ICD 10 - D59.3 , ICD 09 - 283.11, Z34 and V22, O09 and V23). A total of 55 patients were identified of which 2 patients had TTP and 1 had aHUS. Data including demographics, race, gestational age at diagnosis of TMA, timing of ADAMTS13 testing, presence of fever, diarrhea, neurological symptoms, petechiae, bleeding , laboratory data (complete blood count, complete metabolic profile, coagulation panel, LDH ) , peripheral smear results; timing of plasmapheresis(PLEX), use of rituximab/ eculizumab, length of stay, 30 day readmission rate, days required for platelet recovery, number of PLEX sessions conducted were obtained and documented on an excel sheet. Given that 3 patients met study criteria, descriptive analysis was performed. Results: Of the 2 patients with TTP, patient 1 had 5 pregnancies and patient 2 had 1 pregnancy (fig 1). Altered mental status was the common feature in both patients (fig 3). Diagnosis of TTP was made on day 1 with confirmation of diagnosis between day 3-5. They were started on plasma infusion, steroids and plasmapheresis within 24 hrs. Response to treatment was variable with time to platelet recovery ranging between 3-10 days. Both patients remained in remission while not pregnant. Amongst the 6 pregnancies between them 1 resulted in Intrauterine Fetal Death, 2 elective abortions and 3 live births. Maternal survival was 100%. Patient 1 was eventually found to have ADAMTS 13 inhibitor and sarcoidosis and none of them had congenital TTP. Patient 3 presented with features of HELLP at 31 week of gestation and had emergent c- section after which she developed acute kidney injury, worsening thrombocytopenia and anemia. Was initially treated for TTP and started on PLEX, with minimal response after 5 sessions. ADAMTS 13 >35% and kidney biopsy showed TMA. She was diagnosed with aHUS and started on eculizumab, after which she showed clinical improvement. Subsequent follow up showed that there were no long-term health concerns in the children. Discussion: The diagnosis of TTP and aHUS during pregnancy can be challenging, as this condition mimics several other diseases like HELLP and acute fatty liver of pregnancy. Owing to the devastating nature, it is imperative to make the right diagnosis in a timely manner. Hematologists are often also asked to estimate risk of recurrence of TTP during pregnancy and also impact on the pregnancy itself. Jiang et al using the Oklahoma (TTP-HUS) Registry showed that women with a previous history of TTP, the frequency of recurrence is low and pregnancy outcomes are positive. Our review showed favorable outcome of pregnancy in patients with TTP and aHUS when diagnosis is made in a timely manner and treated appropriately i.e, PLEX within 24 hours of diagnosis. Our study also demonstrates that in patients with aHUS, PLEX stabilized the patient, but complete response is achieved only with Eculizumab, a humanized recombinant monoclonal antibody that inhibits the terminal pathway of complement activation by blocking the activation of complement protein C5. Without eculizumab, the abnormal pattern of complement activation and TMA are likely to persist with the risk of irreversible organ damage. Our study has limitations owing to the small study population. TTP and aHUS in pregnancy are however very rare and we hope to add to the existing literature. Disclosures Rajasekhar: Alexion: Membership on an entity's Board of Directors or advisory committees; Bayer: Membership on an entity's Board of Directors or advisory committees; Octapharma: Membership on an entity's Board of Directors or advisory committees; Kedrion Biopharma: Membership on an entity's Board of Directors or advisory committees; ABIM: Other: direct payment for serving on Hematology Board Question Writing Task Force.

Caplacizumab treatment for acquired thrombotic thrombocytopenic purpura (HERCULES trial).

In people with acquired thrombotic thrombocytopenic purpura (TTP), does caplacizumab decrease the time to normalisation of the platelet count and the risk of death and complications caused by thrombotic events and organ damage? In adults with acquired TTP, caplacizumab decreased the time to normalisation of the platelet count and decreased the risk of TTP-related death and recurrence of TTP.

Prevention of relapse in patients with acquired thrombotic thrombocytopenic purpura undergoing elective surgery: a case series

Essentials Thrombotic thrombocytopenic purpura (TTP) is a life-threatening disease. Surgery is a possible trigger of acute TTP episodes and no guidelines are available. Six patients with severe ADAMTS-13 deficiency during remission underwent elective surgery. Patients were prophylactically treated to restore ADAMTS-13 activity and no relapses occurred. SUMMARY: Background Severe ADAMTS-13 deficiency has been recognized as the main risk factor for recurrence of thrombotic thrombocytopenic purpura (TTP). Several conditions, including surgery, may influence the levels of ultra-large von Willebrand factor and ADAMTS-13, acting as a trigger for an acute TTP event. Objectives To report our experience of management of six patients with acquired TTP who underwent elective surgery after prophylactic treatment to restore ADAMTS-13 activity levels. Patients Six patients followed for acquired TTP with severe ADAMTS-13 deficiency during remission were candidates for seven elective surgeries (inguinal hernioplasty, cholecystectomy, laparoscopic hysterectomy, oophorectomy, parotidectomy and two total hip arthroplasties). Results Four patients were treated with prophylactic plasma exchange (PEX) therapy immediately before surgery. One patient was treated with PEX therapy before her first surgery and with preemptive rituximab once her second surgery was scheduled. Because rituximab increased ADAMTS-13 levels only partially, she required one PEX procedure the day before her second surgery. One patient was treated with azathioprine after rituximab failure, obtaining a progressive increase of ADAMTS-13 activity to more than 40%. This level allowed her to undergo total hip arthroplasty without additional treatment. All surgeries were successful and no complications or relapses occurred. Conclusions Six patients with acquired TTP underwent seven successful surgical procedures using prophylaxis to restore ADAMTS-13 activity. Further observational studies or randomized clinical trials are needed to confirm whether prophylactic PEX could be the key factor in preventing relapse.

Caplacizumab Treatment for Acquired Thrombotic Thrombocytopenic Purpura

BackgroundIn acquired thrombotic thrombocytopenic purpura (TTP), an immune-mediated deficiency of the von Willebrand factor–cleaving protease ADAMTS13 allows unrestrained adhesion of von Willebrand factor multimers to platelets and microthrombosis, which result in thrombocytopenia, hemolytic anemia, and tissue ischemia. Caplacizumab, an anti–von Willebrand factor humanized, bivalent variable-domain-only immunoglobulin fragment, inhibits interaction between von Willebrand factor multimers and platelets.MethodsIn this double-blind, controlled trial, we randomly assigned 145 patients with TTP to receive caplacizumab (10-mg intravenous loading bolus, followed by 10 mg daily subcutaneously) or placebo during plasma exchange and for 30 days thereafter. The primary outcome was the time to normalization of the platelet count, with discontinuation of daily plasma exchange within 5 days thereafter. Key secondary outcomes included a composite of TTP-related death, recurrence of TTP, or a thromboembolic event during the trial treatment period; recurrence of TTP at any time during the trial; refractory TTP; and normalization of organ-damage markers.ResultsThe median time to normalization of the platelet count was shorter with caplacizumab than with placebo (2.69 days [95% confidence interval {CI}, 1.89 to 2.83] vs. 2.88 days [95% CI, 2.68 to 3.56], P=0.01), and patients who received caplacizumab were 1.55 times as likely to have a normalization of the platelet count as those who received placebo. The percentage of patients with a composite outcome event was 74% lower with caplacizumab than with placebo (12% vs. 49%, P<0.001). The percentage of patients who had a recurrence of TTP at any time during the trial was 67% lower with caplacizumab than with placebo (12% vs. 38%, P<0.001). Refractory disease developed in no patients in the caplacizumab group and in three patients in the placebo group. Patients who received caplacizumab needed less plasma exchange and had a shorter hospitalization than those who received placebo. The most common adverse event was mucocutaneous bleeding, which was reported in 65% of the patients in the caplacizumab group and in 48% in the placebo group. During the trial treatment period, three patients in the placebo group died. One patient in the caplacizumab group died from cerebral ischemia after the end of the treatment period.ConclusionsAmong patients with TTP, treatment with caplacizumab was associated with faster normalization of the platelet count; a lower incidence of a composite of TTP-related death, recurrence of TTP, or a thromboembolic event during the treatment period; and a lower rate of recurrence of TTP during the trial than placebo. (Funded by Ablynx; HERCULES ClinicalTrials.gov number, NCT02553317.)

Efficacy of Adjuvant Low Dose Rituximab and Plasma Exchange for Acquired TTP with Severe ADAMTS13 Deficiency — Results of the ART Study

▪Introduction:Acquired thrombotic thrombocytopenic purpura (TTP) is caused by autoantibodies against ADAMTS13 that prevent the cleavage of von Willebrand factor and allow the growth of microvascular thrombi, causing microangiopathic hemolysis and severe thrombocytopenia. Untreated TTP is almost always fatal but plasma exchange enables ~80% of patients to survive. Those who respond often have exacerbations or relapses that require more therapy. Exacerbations and refractory TTP usually can be treated effectively by combining plasma exchange, corticosteroids, and rituximab. A typical regimen for TTP is 4 weekly doses of rituximab 375 mg/m2, which is borrowed from protocols for B cell lymphomas. However, the pathogenic B cell mass in TTP is much less than in lymphoma and lower doses of rituximab may be enough. For example, case reports in TTP and studies in immune thrombocytopenia suggest that fixed doses of 100 mg and conventional doses of 375 mg/m2 have similar efficacy.Methods:The ART study (Adjuvant Rituximab in TTP, NCT01554514) was designed as a pilot safety/efficacy study of low dose rituximab (100 mg/week x 4 doses) plus standard plasma exchange and corticosteroids for TTP. The study enrolled at Washington University, Beth-Israel Deaconess Medical Center, Emory University, and Duke University. Eligibility criteria include age ≥18 years with acute TTP and ADAMTS13 <10%. Exclusions include treatment for TTP within 2 months, severe infection, cancer, organ or stem cell transplant, pregnancy, hepatitis B, and use of calcineurin inhibitors within 6 months or rituximab within the past year. Treatment included daily 1.5 volume plasma exchanges, prednisone 1 mg/kg, and rituximab 100 mg weekly for 4 doses starting before the 5thplasma exchange. Treatment Response is defined as 2 consecutive days with a platelet count ≥150,000/µl. A Durable Treatment Response persists ≥30 days after stopping plasma exchange. The primary endpoint is a composite of Exacerbation or Refractory TTP, where Exacerbation is recurrence of TTP ≤30 days after a treatment response and Refractory TTP is failure to achieve a Treatment Response by day 28 or failure to achieve a Durable Treatment Response by day 60.Secondary endpoints include the relapse rate at 2 years.Results:19 patients were enrolled. Two patients were subsequently excluded: 1 proved to have congenital TTP and was ineligible, 1 was withdrawn for protocol violations during the first week. The 17 evaluable patients have a median age of 48 years (range 30-71), 14 (82%) are African-American and 11 (65%) are female. All had a treatment response in a median of 5 days (range 3-16 days). 13 patients achieved normal ADAMTS13 levels after treatment, 2 had persistent severe ADAMTS13 deficiency, and 2 patients have yet to be assessed for ADAMTS13 responses. No patients had refractory disease and 2 had exacerbations; both achieved Durable Treatment Responses after 29 and 35 days. No patient died of TTP; 1 patient died of metastatic cancer. To date, 13 patients have completed 2 years of follow up and 3 (23%)have relapsed at 11, 19, and 22 months. For comparison, among 54 episodes of TTP at Washington University treated without rituximab, the primary endpoint occurred in 26 (48%). These included exacerbation in 23 (43%), refractory disease in 9 (17%), and both in 6 (11%). 6 patients died, and the incidence of relapse within 2 years was 51%. Treatment with low dose rituximab (100 mg) was associated with a significant decrease in the primary endpoint from 48% to 12% (P= 0.01, Fisher's exact test) and an encouraging decrease in 2-year relapse rate from 51% to 23% (P= 0.06).Conclusions:These results with low dose rituximab (100 mg x 4 doses) are consistent with reports that immediate treatment of TTP with standard dose rituximab (375 mg/m2x 4 doses) reduces the incidence of exacerbation and refractory disease, and prevents or delays relapses. A direct comparison of these regimens would be useful to establish whether low dose rituximab has similar efficacy with greater ease of administration, less cost, and less risk of infusion reactions and late complications. DisclosuresSadler:Ablynx: Consultancy. Zwicker:Quercegen: Research Funding; Daiichi: Honoraria; Parexel: Consultancy; Incyte: Research Funding.

Investigator-Initiated Phase 2 Trial of Rituximab in Adult Japanese Patients with Treatment-Resistant Acquired Thrombotic Thrombocytopenic Purpura

About 500 persons in Japan are estimated to have thrombotic thrombocytopenic purpura (TTP), which is a life-threatening disorder. In contrast with the USA and EU, off-label use of rituximab for TTP is not allowed by the Japanese public health insurance system. We therefore have limited experience of the effects of rituximab in Japanese patients with adult TTP and have not investigated possible ethnicity-related differences in its effects. To evaluate the safety and efficacy of rituximab in Japanese adult patients with TTP, we conducted an investigator-initiated phase 2 clinical trial in Japan between January and December of 2014. This study was sponsored by the Japanese government and the study design was based instructions from the regulatory agency, PMDA (Phamaceuticals and Medical Devices Agency). Adult Japanese patients with acquired TTP that had proven refractory to at least five plasma exchanges (PEX) or had serum concentrations of more than 2 BU/mL of ADAMTS13 inhibitor or both were eligible for this study. Rituximab was infused at 375 mg/m2 weekly for 4 weeks. The study protocol allowed use of both plasma exchange and corticosteroids with the investigational drug. Thirteen patients were registered and seven found to be eligible and treated with rituximab. All seven patients were evaluable for safety and six for efficacy. Three of these six (50%) were women; the median age was 41.5 years. Median platelet counts at baseline were 22 × 109/L. All of these six patients were refractory to previous PEX and ADMTS13 inhibitor concentrations were higher than 2 BU/mL in two (33%) of them. All six patients no longer required PEX after receiving rituximab treatment. Five (83%) and two (33%) patients achieved platelet counts of 100 × 109/L and 150 × 109/L 4 weeks after initiating rituximab, respectively. Median platelet counts at week 4 after commencing rituximab were 136 × 109/L (range: 64-201 × 109/L). The median time from initiating PEX to achieving platelet counts over 150 × 109/L was 22 days. By the study endpoint (4 weeks after initiating rituximab treatment), ADAMTS13 activity had normalized to 77.3% from 3.4%, accompanied by disappearance of ADAMTS13 inhibitor. Both anemia and neurological impairment also improved in all patients. The median percentages of peripheral blood CD20-positive B cells were 22.9% and 0.2% before and at the completion of treatment with rituximab, respectively. Serum IgG decreased slightly from 1,116 mg/dL at baseline to 921 mg/dL 4 weeks after rituximab treatment. Five of seven patients experienced adverse events, two of which were severe; namely septic shock and cytomegalovirus infection; no patients died. No unpublished severe adverse events were noted. No recurrence of TTP occurred during a median follow-up of 7 months. These data suggest that rituximab is safe and effective for acute refractory/high risk acquired TTP in Japanese patients and that there are no ethnic differences in effectiveness or safety of rituximab for adult TTP. However, there were too few patients to draw any firm conclusions. Further investigation is necessary to optimize the treatment schedule of rituximab. We are preparing to apply to the Japanese regulatory agency for approval of new indications for rituximab for TTP. DisclosuresOff Label Use: Investigational drug, rituximab, was provided by Zenyaku Kogyo Co. Ltd.. Matsumoto:Baxter Bioscience: Consultancy.

Thrombotic thrombocytopenic purpura precipitated by thyrotoxicosis

Thrombotic thrombocytopenic purpura (TTP) may be seen in association with autoimmune disorders such as immune hemolytic anemia and systemic lupus erythematosus, but rarely has it been associated with Graves' disease. We report one such case of a woman with new-onset thyrotoxicosis caused by Graves' disease, who abruptly developed TTP, confirmed by low serum ADAMTS-13 value. She had a dramatic response to plasma exchange, with remission of TTP. Definitive treatment with radioactive iodine resulted in euthyroidism and has prevented recurrence of TTP.

Case report: use of thienopyridines in a patient with acquired idiopathic thrombotic thrombocytopenic purpura

Thienopyridines are commonly used anti-platelet drugs that may be associated with the development of secondary, drug-induced thrombotic thrombocytopenic purpura (TTP), a rare but potentially life threatening condition. We report the case of a 70year-old man with a history of recurrent idiopathic TTP episodes who was treated with clopidogrel and then ticlopidine for thromboprophylaxis after percutaneous coronary intervention. Treatment was successful with no signs of TTP recurrence. Platelet counts and ADAMTS13 activity levels remained normal for months after the initiation of anti-platelet therapy, with no reappearance of anti-ADAMTS13 autoantibodies. This report demonstrates that thienopyridines do not necessarily induce TTP in patients with a history of TTP who are in disease remission.

Successful prevention of thrombotic thrombocytopenic purpura (TTP) relapse using monthly prophylactic plasma exchanges throughout pregnancy in a patient with systemic lupus erythematosus and a prior history of refractory TTP and recurrent fetal loss

Background The occurrence of thrombotic thrombocytopenic purpura (TTP) in the setting systemic lupus erythematosus (SLE) is rare. In women of childbearing age, TTP is associated with high rates of recurrence in pregnancy. Furthermore, both TTP and SLE are associated with a significant risk of adverse pregnancy outcomes. Case presentation We describe the case of a 36 year old female in her first trimester of pregnancy with a prior history of SLE-associated severe refractory TTP who was treated with a combination of corticosteroids and prophylactic plasma exchanges (PLEX) throughout pregnancy to prevent TTP recurrence. She delivered a healthy infant at 33 weeks of gestation after the onset of preterm labor. There was no evidence of TTP recurrence in the antepartum or postpartum period in this high risk patient. Conclusion Prophylactic PLEX should be considered as a therapeutic option to prevent recurrent TTP during pregnancy in high risk patients, including patients with previous SLE-associated TTP.

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

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

Thrombotic thrombocytopenic purpura during immune reconstitution

The emergence of newer antiretroviral agents has revolutionized the treatment of patients struggling with multidrug-resistant strains of HIV. As a result, we are witnessing a higher incidence of immune reconstitution inflammatory syndrome, most commonly associated with mycobacterial, cryptococcal, herpetic and other infections, in addition to autoimmune conditions such as photodermatitis, systemic lupus erythematosus [1], Grave's thyroiditis [2] and sarcoid [3]. The pathogenesis of immune reconstitution inflammatory syndrome is unclear, but has been proposed to be a combination of thymic-independent homeostatic peripheral expansion, immune dysregulation between effector and regulatory T cells, increased inflammatory cytokines and dysregulated dendritic cells [4,5]. We present the case of a 48-year-old African-American man, with multiple drug-resistant HIV-1 infection, who was admitted to the hospital with acquired thrombotic thrombocytopenic purpura (TTP) 4 weeks after darunavir/norvir and enfuvirtide was added to tenofovir/emtricitabine. The patient had a past medical history only significant for chronic hepatitis B, with an undetectable viral load. After 4 weeks on the new regimen, his CD4 cell count increased from 94 (10%) to 351 (16.7%) cells/μl and his viral load decreased from more than 100 000 to 151 copies/ml. He presented with a non-productive cough, frontal headache, dark urine, dyspnea on exertion, myalgias and arthralgias from a previously asymptomatic state. Laboratory work-up (baseline in parenthesis) showed a hemoglobin level of 7.4 g/dl (11.2), platelets of 22 × 103/μl (221), lactate dehydrogenase 2450, creatinine 1.8 mg/dl (1.2), and a peripheral smear showed many schistocytes. An assay (Esoterix Inc., Austin, Texas, USA) showed the von Willebrand factor (vWF) cleaving protease to be deficient (< 8%), and the presence of a disintegrin-like and metalloprotease with thrombospondin-type 1 motif-13 (ADAMTS-13) vWF cleaving protease inhibitor (1.2 inhibitor units). No other inciting event was identified after extensive work-up. All his antiretroviral drugs were discontinued except for tenofovir/emtricitabine, whereas plasmapharesis, vincristine and prednisone were initiated. He had a full and uneventful recovery one month later. Subsequently, our patient was successfully restarted on antiretroviral therapy (darunavir/norvir and tenofovir/emtricitabine) without a recurrence of TTP, while experiencing increasing CD4 cell counts and decreasing viral loads. Although TTP has been described in relation to HIV [6], to our knowledge this is the first reported case of acquired TTP in the setting of immune reconstitution. Our patient had a low absolute CD4 cell count and CD4 cell percentage at baseline, followed by a ‘fulminant’ CD4 cell count recovery and viral suppression shortly after starting his new regimen. A Medline search failed to identify any association between TTP and antiretroviral agents, i.e. T-20, darunavir and others. Although a causal mechanism cannot be established from one case, we propose two insults accounting for a major alteration of vWF homeostasis based on previous descriptions of TTP [7]. The first alteration was caused by inflammatory cytokines (IL-6, IL-8, tumour necrosis factor alpha and others) that stimulate the ultralarge, hyperreactive vWF release from endothelial cells. The second insult is immune deregulation mediated by IL-6 and other autoantibodies that inhibit (ADAMTS-13) vWF cleaving protease activity, abrogating the ability of ADAMTS-13 to cleave ultralarge vWF, leading to the accumulation of ultralarge vWF in plasma and on the surface of endothelial cells. Could these two hits combined account for the high tendency for platelet aggregation and thrombosis that patients might be at risk of during the acute phase of immune reconstitution? The second reason we believe this case to be notable is its possible implication in the increase in cardiovascular events after immune reconstitution (unpublished). We believe that further studies should investigate the role of thrombosis in the increased cardiovascular events after acute immune reconstitution.

Risk Factors for Recurrence of Thrombotic Thrombocytopenic Purpura.

The introduction of plasma exchange therapy in early 1970s significantly reduced the rate of mortality in patients affected by thrombotic thrombocytopenic purpura (TTP), a disease characterized by thrombocytopenia and microangiopathic hemolytic anemia. A similar improvement was never achieved in the prevention of the disease recurrence. Still, 20–50% of patients, who survived the fatal disease, experience a relapse one month or even years after the acute episode of TTP. There is no pathognomic marker or laboratory test that can be used for the surveillance of TTP during remission and predict which patients will relapse.We have retrospectively analyzed for the first time at remission the role of ADAMTS13, anti-ADAMTS13 autoantibodies and von Willebrand Factor (VWF) in 109 patients who survived the acute episode of TTP. ADAMTS13 activity and ADAMTS13 antigen levels were measured as described by Gerritsen et al (TH 1999) and Feys HB et al. (JTH 2006), respectively. The total anti-ADAMTS13 autoantibodies (with and without neutralizing activity) were measured by western blot analysis and the presence of neutralizing anti-ADAMTS13 autoantibodies was checked according to Gerritsen et al (TH 1999). VWF antigen was measured using an ELISA assay and VWF multimers analysis was carried out using low-resolution SDS-agarose gel electrophoresis and exposing gels to human anti-VWF antibodies labeled with I125 for autoradiography (Ruggeri & Zimmerman, Blood 1981). All variables have been statistically analyzed in 2 subgroups of patients with or without TTP recurrence, in order to understand the role of each variable as a potential predictor marker for recurrence. Univariate and multivariate analysis were carried out to evaluate adjusted and unadjusted odds ratios (Ors) with 95% confidence intervals (CI) as a measure of the relative risk of relapse associated with the risk factors under investigation.Our data showed that the median value of ADAMTS13 activity and antigen levels at remission were significantly lower in patients with recurrent TTP than in patients with no relapse (ADAMTS13 activity: 12% vs. 41%; p=0.007; ADAMTS13 antigen: 36% vs 58%; p=0.003). Furthermore, the prevalence of patients with severe ADAMTS13 deficiency (≤10%) was significantly higher in the group of patients who relapsed (OR=2.9 CI95% 1.3–6.8, p=0.01). The prevalence of anti-ADAMTS13 autoantibodies (with or without neutralizing activity) resulted to be significantly higher in patients with recurrent TTP (OR= 3.1 CI 95% 1.4–7.3, p=0.006). A higher VWF antigen levels or the presence of ultralarge VWF (ULVWF) multimers at remission did not increase the risk of recurrence (p=0.4 for VWF:Ag and p=0.7 for ULVWF multimers).In conclusion, our data showed that the association of severe ADAMTS13 deficiency and the presence of anti-ADAMTS13 autoantibodies is a negative prognostic marker at remission and increases the relative risk of TTP recurrence by 3.6 times (OR=3.6 CI95% 1.4–9). Therefore our results would suggest that our efforts should go in the direction of maintenance therapy which aims at reducing or abolishing the presence of antibodies during remission and increasing the level of ADAMTS13 in plasma in order to prevent the recurrence of TTP.

An evaluation of ciclosporin and corticosteroids individually as adjuncts to plasma exchange in the treatment of thrombotic thrombocytopenic purpura

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.

Recurrent Idiopathic Thrombotic Thrombocytopenic Purpura: A Role for Vaccination in Disease Relapse?

The presence of antibodies against a disintegrin-like metalloproteinase with thrombospondin type 1 motif, isoform 13 (ADAMTS 13 protease) is the main cause (70% to 80%) of idiopathic and recurrent thrombotic thrombocytopenic purpura (TTP). However, etiologic factors that trigger the onset and potential relapses of TTP remain unclear. Immunologic deregulation and infectious agents are suspected. We report the case of a 51-year-old white man presenting with idiopathic TTP caused by autoantibodies against ADAMTS 13 protease. The first acute TTP episode needed long-term plasma exchanges because of early relapses. Consequently, vincristine therapy and splenectomy were performed. Those treatments induced TTP remission for 18 months. Relapses occurred twice between 1 and 3 months after vaccination. However, those relapses were not as severe as the first acute episode and responded to short-course plasma exchanges. ADAMTS 13 antibodies and decreased ADAMTS 13 protease activity were searched for and detected first during the second relapse. This case challenges the role of vaccination as an etiologic factor in the recurrence of idiopathic TTP.

A case of systemic lupus erythematosus associated with thrombotic thrombocytopenic purpura and hemophagocytic syndrome

A 44-year-old female. Developed polyarthralgia in August 2002. The patient was diagnosed with systemic lupus erythematosus (SLE) in November, due to polyarthralgia, leukopenia, anti ds-DNA antibody positive, antinuclear antibody positive, and false positive serologic test for syphilis. Hypocomplementemia continued even after the steroid treatment was conducted with insufficient control. In November 2003, ran fever and observed polyarthralgia. In December, gross hematuria and purpura appeared. The patient was hospitalized on December 25. Thrombotic thrombocytopenic purpura (TTP) was suspected from the emergence of fragmented red cells, hemolysis, thrombocytopenic purpura, headache, renal dysfunction and fever. As hemophagocytic syndrome (HPS) was suspected from hyper-ferritinemia, bone marrow aspiration was conducted. Macrophage confirmed hemophagocytic image and the patient was diagnosed with HPS complication. Methylprednisolone pulse therapy was conducted for three days, followed by the administration of prednisolone 60 mg. Plasma exchange therapy was also conducted from the first day of hospitalization. Recurrence of TTP after plasma exchange therapy, but it improved by additional plasma exchange. Low vWF-CP (ADAMTS-13) activity was observed in this case, and anti-vWF-CP antibody was positive. TTP and HPS are both critical intractable complications of SLE. Bearing in mind the possibility of simultaneous complication of both symptoms, prompt diagnosis is crucial for life-saving.

Rituximab prevents recurrence of thrombotic thrombocytopenic purpura: a case report

AbstractThrombotic thrombocytopenic purpura (TT666666) is a rare disorder of small vessels that is associated with deficiency of the von Willebrand factor–cleaving protease, ADAMTS13. The presence of anti-ADAMTS13 autoantibodies is considered a factor predisposing to relapses. Despite close monitoring and intensive plasma treatment, in these patients acute episodes are still associated with substantial morbidity and mortality rates, and the optimal therapeutic option should be prevention of relapses. This study was conducted in a patient with recurrent TTP due to high titers of ADAMTS13 inhibitors, who used to have 2 relapses of TTP a year. The study compared the standard treatment plasma exchange with rituximab. Results documented that plasma exchange had only a small transient effect on ADAMTS13 activity and inhibitors; on the contrary, prophylaxis with rituximab was associated with disappearance of anti-ADAMTS13 antibodies, a progressive recovery of protease activity, and it allowed the patient to maintain a disease-free state during a more than 2-year follow-up.

Thrombotic Thrombocytopenic Purpura Without Schistocytes on the Peripheral Blood Smear

A hallmark of the clinical syndrome of thrombotic thrombocytopenic purpura (TTP) is evidence of microangiopathic hemolytic anemia. The presence of schistocytes on the peripheral blood smear, elevated plasma lactic dehydrogenase, and decreased haptoglobin concentration are used as evidence of microangiopathic hemolytic anemia to make a diagnosis of TTP. This report describes a case of recurrence of TTP in the absence of schistocytes in the peripheral blood smear during the recurrent episode. Although careful attention should be paid to microscopic examination of a blood smear in any patient presenting with acute renal failure and thrombocytopenia, this case emphasizes the need to consider TTP-hemolytic uremic syndrome in the differential diagnosis, even in the absence of peripheral schistocytosis.

Relapse of Thrombotic Thrombocytopenic Purpura: Is It a Continuum of Disease?

The recurrence of thrombotic thrombocytopenic purpura (TTP) in 20 to 50% of patients who survive their initial episode, is not only a challenge to manage clinically, but brings to light our lack of understanding of the underlying pathophysiology. Recurrence may occur close to apparent hematologic remission or remotely, months later. Given that surveillance of TTP relies on surrogate measures such as hematologic recovery, normalization of serum lactate dehydrogenase (LDH) and resolution of clinical signs, it is plausible that some recurrences are actually a continuum of disease. Standardizing definitions for remission, exacerbation, and relapse are important for consistency of patient management and interpreting the medical literature. When TTP recurs, several adjuncts to therapeutic plasma exchange (TPE) have been used, including splenectomy, vincristine, and rituximab. Although it would seem intuitive that more severe disease would predict a greater likelihood of relapse, the degree of thrombocytopenia at presentation, the persistence of schistocytosis at discontinuation of TPE, the elevation of LDH, and the length of time to attain clinical remission are not reliable indicators of the clinical outcome of any individual TTP patient. Measurement of ADAMTS13 activity and its inhibitor offer new promise for prognostic and pathophysiologic significance; however, more extensive scientific investigation is needed.