Severe Thrombotic Thrombocytopenic Purpura Research Articles

A Real-World Analysis of Acquired Thrombotic Thrombocytopenic Purpura: Comparing Clinical Outcomes of Early Versus Late Responders to Plasma Exchange

INTRODUCTION: Acquired thrombotic thrombocytopenic purpura (TTP) is a rapidly fatal thrombotic microangiopathy mediated by autoantibodies targeting ADAMTS-13. The main pillars of acquired TTP management include therapeutic plasma exchange (PLEX) and immunosuppression with glucocorticoids and rituximab. PLEX is initiated in all patients with a presumptive clinical/confirmed diagnosis of TTP and is continued until platelet count recovery. The platelet response to PLEX is quite variable, with some patients having rapid recovery (early responders [ERs]) within 4-7 days, and others requiring a longer duration (late responders [LRs]) of PLEX. Although rapid platelet count recovery is reassuring to the treating physician, it is unclear whether there is a significant difference in outcomes between ERs and LRs to PLEX. We performed a single-center retrospective study of survival outcomes of ERs vs those of LRs with acquired TTP. METHODS: We performed a retrospective analysis of adult patients (≥18 years old) with acquired TTP who were treated at our institution between January 1, 2005, and May 1, 2020. Baseline demographic and clinical data and laboratory values at the time of diagnosis were collected. Patients were ERs if platelet recovery (platelet count >150,000/µL for 2 consecutive days) occurred within 7 days of starting PLEX, whereas LRs had delayed platelet recovery (≥7 days) after initiation of PLEX. Refractory disease was defined as recurrent thrombocytopenia (platelet count <150,000/µL) following an initial response between days 1 and 30 after last PLEX. Relapses were defined as thrombocytopenia and elevated LDH occurring >30 days after last PLEX. We analyzed survival outcomes and the relapse risk in ERs versus LRs. RESULTS: A total of 61 patients fulfilled the diagnostic criteria for acquired TTP (ER = 34 patients, LR = 27 patients). Patient demographics, laboratory studies, and treatment details are shown in Table 1. The mean age of ER and LR patients was 45 and 38 years, respectively. About 56% of patients in each group identified as Black. About 18% of ERs and 9% of LRs had a diagnosis of HIV. No statistically significant difference was noted in the baseline laboratory findings of the two groups. Involvement of ≥2 affected organ systems was seen in 79% of ERs and 93% of LRs (p=0.2757). All LRs (100%) and 88% of ERs had severe TTP at presentation (ADAMTS-13 level ≤10). The mean number of PLEX was 6.11 and 24.96 in ERs and LRs (p<0.0001), respectively. The mean number of PLEX to platelet recovery was 4.27 and 19.27 (p<0.0001). Glucocorticoids were given to 97% of ERs and 100% of LRs. First-line rituximab was given to 52% (n=14) of LRs, versus only 9% (n=3) of ERs (p=0.0004). About 15% of LRs went on to receive additional immunosuppressive agents, whereas no ERs did so (p=0.0336). The relapse rate among ERs and LRs was 55.56% and 44.44%, respectively (p > 0.9999). The 30-day mortality rate was 6% in ERs and 0% in LRs. Cardiovascular diseases were the common cause of early deaths. Overall survival (OS) at 6 months was 79% in ERs and 96% in LRs (p=0.0665). The OS at 1 year was 74% in ERs and 96% in LRs (p=0.03). The 2-year OS was available for 24 ER patients (83%) and LR 17 patients (89%) (p>0.9999). Among the 19 patients who received front-line rituximab, the OS at 1 year was 100%. CONCLUSIONS: More LRs than ERs received rituximab and glucocorticoids for immunosuppression as first-line therapy. LRs were found to have a statistically significant greater OS at 1 year. ERs were less likely to receive adequate immunosuppression than LRs. This may indicate that the time to response to PLEX should not be used as a surrogate for risk of relapse. Immunosuppression is the cornerstone of the management of acquired TTP, and first-line use of rituximab is critical in the reducing relapse rate and improving OS. Larger studies in the prospective setting are needed to evaluate the impact of duration of PLEX on OS. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

Severe Thrombotic Thrombocytopenic Purpura (TTP) with Organ Failure in Critically Ill Patients.

Thrombotic thrombocytopenic purpura (TTP) is a multiorgan disorder. Organ dysfunction occurs as a consequence of widespread microvascular thrombosis, especially in the heart, brain and kidney, causing transient or partial occlusion of vessels, resulting in organ ischemia. Intensive care unit (ICU) admission varies between 40% and 100% of patients with TTP, either because of severe organ failure or in order to initiate emergency plasma exchange (PEx). Severe neurologic manifestations and cardiac involvement have been associated with higher mortality. Acute kidney injury, although usually less severe than that in hemolytic and uremic syndrome, is common during TTP. Initial management in the ICU should always be considered in TTP patients. The current treatment of TTP in the acute phase is based on urgent PEx, combined with corticosteroid therapy, B-cell-targeted immunotherapy, rituximab and inhibition of the interaction between ultra-large Von Willebrand factor multimers and platelets, using caplacizumab, a monoclonal antibody. ICU management permits close monitoring and the rapid introduction of life-sustaining therapies. This review details the epidemiology of TTP in the ICU, organ failures of critically ill patients with TTP, and the initial management of TTP patients in the ICU.

Rituximab related non-infectious lung injury complicating treatment of severe TTP in pregnancy – literature review and case-report

Background: Thrombotic thrombocytopenic purpura (TTP) in pregnancy is a rare but potentially life-threatening condition. Management of severe, refractory TTP during pregnancy is challenging and includes multidisciplinary approach. The prognosis of cases with a variety of hematological and autoimmune diseases, including TTP has changed profoundly after the rituximab therapy was introduced into clinical practice. However, adverse pregnancy outcomes associated with biological agents should be kept in mind and the decision to treat should be weighed by measurement of potential risks vs benefits. Case report: We reported the first documented case of noninfectious lung toxicity in pregnancy related to rituximab use for TTP treatment. 26 y/o patient at 23 weeks gestation initially presented to ED secondary to numbness, headache, and slurred speech with negative brain imaging. Her laboratory findings revealed severe deficiency of platelets, hemoglobin and ADAMT13 activity. She underwent multiple therapeutic interventions including plasmapheresis, intravenous immunoglobulins (IVIG), prednisone, and eventually required more often hospitalizations. Ultimately, the decision was made to proceed with rituximab therapy. After the third infusion of rituximab, she developed non-infectious lung injury without evidence of SARS-CoV-2 or other infections, pulmonary edema, or pulmonary embolism. The maternal condition worsened acutely resulting in significant desaturation that required intubation and eventual emergent premature delivery at 31-weeks’ gestation via C-section. Conclusion: Rituximab therapy for TTP management in pregnancy may be associated with significant adverse maternal-fetal outcomes. Risks and benefits of treatment should be discussed with each patient and during multidisciplinary communications. Physicians should maintain high index of suspicion for non-infectious lung injury associated with rituximab treatment in order to be able to diagnose this complication early and start treatment to avoid severe mortality and morbidity.

Outcomes in 1096 patients with severe thrombotic thrombocytopenic purpura before the Caplacizumab era.

IntroductionThrombotic thrombocytopenic purpura (TTP) is a diagnostic and therapeutic emergency. Therapeutic plasma exchange (TPE) combined with immunosuppression has been the cornerstone of the initial management. To produce optimal benefits, emerging treatments must be used against a background of best standard of care. Clarifying current uncertainties is therefore crucial.MethodsThe objective of this study was to analyze a large high-quality database (Marketscan) of TTP patients managed between 2005 and 2014, in the pre-caplacizumab era, in order to assess the impact of time to first TPE and use of first-line rituximab on mortality, and whether mortality declines over time.ResultsAmong the 1096 included patients (median age 46 [IQR 35–55], 70% female), 28.8% received TPE before day 2 in the ICU. Hospital mortality was 7.6% (83 deaths). Mortality was independently associated with older age (hazard ratio [HR], 1.024/year; 95% confidence interval [95%CI], [1.009–1.040]), diagnosis of sepsis (HR, 2.360; 95%CI [1.552–3.588]), and the need for mechanical ventilation (HR, 4.103; 95%CI, [2.749–6.126]). Factors independently associated with lower mortality were TPE at ICU admission (HR, 0.284; 95%CI, [0.112–0.717]), TPE within one day after ICU admission (HR, 0.449; 95%CI, [0.275–0.907]), and early rituximab therapy (HR, 0.229; 95% CI, [0.111–0.471]). Delayed TPE was associated with significantly higher costs.ConclusionsImmediate TPE and early rituximab are associated with improved survival in TTP patients. Improved treatments have led to a decline in mortality over time, and alternate outcome variables such as the use of hospital resources or longer term outcomes therefore need to be considered.

Caplacizumab As Step-up Therapy in Refractory TTP Utilizing Adamts-13 Activity and Evidence of End-Organ Damage

Background: Thrombotic Thrombocytopenic Purpura (TTP) is a form of microangiopathic hemolytic anemia that is classically characterized by the clinical pentad of fever, hemolytic anemia, thrombocytopenia, renal dysfunction, and neurologic dysfunction. The pathophysiology of acquired TTP is marked by autoantibody formation against ADAMSTS13, an enzyme responsible for breaking down von Willebrand Factor (vWF) multimers. Standard therapy for TTP includes both replenishing functional ADAMTS-13 and immune-modulation with plasma-exchange and steroids/rituximab, respectively. A novel therapy addresses the microvascular thrombosis hallmark of end-organ damage in TTP. Caplacizumab, a humanized immune globulin that inhibits vWF interaction with platelets, achieved its primary endpoint of faster time to platelet normalization than placebo in the Stage 3 HERCULES trial when given up-front with additional standard therapies. Case Summary: A previously health 26-year-old G3P2 female presented to the ED at 38 weeks gestation with fatigue and confusion. She was found to have a platelet count of 5,000 per microliter, hematocrit of 18.6%, lactate dehydrogenase (LDH) of 1,750 IU/L, and haptoglobin of 11mg/dL. Peripheral blood smear was remarkable for evidence of microangiopathic hemolytic anemia. She had a normal serum creatinine. She was diagnosed clinically with TTP and subsequently underwent emergent caesarian section. She was started on plasma exchange given her ADAMTS13 activity of 6% and features of severe TTP. Her neurological status and platelets initially responded well to plasmapheresis (PE) at 1x volume alone; however, on Day 6 her platelets decreased from 97,000 to 15,000 per microliter. This prompted initiation of both steroids, weekly rituximab and increasing PE to 1.5 x. She continued to be refractory and acutely declined on Day 7, during which she developed worsening headaches followed by seizure, renal failure with proteinuria, uncontrolled hypertension and increasing hemolysis. She required ICU admission and one session of hemodialysis. Despite increasing PE, steroids and rituxan, the patient's inhibitor peaked to 142 U/ml with an ADAMTS-13 activity of 0% on Day 9. PE was increased to 1.5 x volume twice daily. Caplacizumab was obtained and initiated on Day 10. Her platelets on Day 11 were at their nadir of 4,000 per microliter, with an inhibitor of 93.9 and an ADAMTS-13 activity of 0%. She remained in the ICU, where her mental status, renal function improved gradually. She was found with a reticulocyte index of 1.29, for which she was treated with Vitamin B-12 for a methylmalonic acid level of 798 nmol/L (range 87-318 nmol/L) and a low normal level of vitamin B-12. PE was stopped on Day 22 after confirming her platelet level remained &gt;150,000 per microliter for more than three days. Her course was further complicated by aspiration, parainfluenza 3, MSSA bacteremia, and E Coli UTI, for which she received antibiotics and supportive treatment. She completed four cycles of rituximab on Day 27, and was discharged to home with a steroid taper and an additional 21 days of caplacizumab. She was readmitted three times during those 21 days for hemiplegic migraines. She achieved remission with normal complete blood count and ADAMTS13 &gt;109% with an inhibitor 3 on Day 54, after which she was administered her last dose of caplacizumab on Day 56. Discussion: We detail the clinical and treatment course in our patient with severe, acquired TTP from pregnancy. Our timing of caplacizumab administration differed from that in the HERCULES Trial. Rather than administering caplacizumab at the onset of diagnosis, we utilized markers of end-organ damage, ADAMTS13 activity and inhibitor level to gauge the trajectory of the disease process before administering additional therapies. This may represent an alternative approach to treating aTTP in a post-caesarian patient given concern for risk of bleeding and lack of trial data that adequately captures the bleeding risk of this sub-population. Lastly, we describe reticulocytopenia and Vitamin B12 deficiency in this patient complicating her recovery from TTP. The etiology of her B12 deficiency is still unclear ( anti-parietal antibody titer &lt;1:120). Figure Disclosures No relevant conflicts of interest to declare.

TTP AS INITIAL PRESENTATION FOR AN 82-YEAR-OLD FEMALE WITH SYSTEMIC LUPUS

SESSION TITLE: Wednesday Medical Student/Resident Case Report Posters SESSION TYPE: Med Student/Res Case Rep Postr PRESENTED ON: 10/23/2019 09:45 AM - 10:45 AM INTRODUCTION: Thrombotic Thrombocytopenic Purpura (TTP) can be idiopathic or acquired. Most common cause for TTP is illegal drugs, other causes are medications like Quinin, Gemcitabine, oxaliplatin, and quetiapine, or in rare cases it can be secondary to other diseases like connective tissue diseases mostly SLE. We are reporting a case of an 82 y/o Caucasian female who presented with TTP which was found to be secondary to underlying undiagnosed Systemic Lupus Erythematous (SLE). CASE PRESENTATION: 82 y/o F newly diagnosed schizophrenia who presented with generalized fatigue, she was found to have hemoglobin of 4.1 and platelet count of 4000 and creatinine level of 1.8. Lab work for hemolysis showed high LDH, low Haptoglobin, and schistocytes where seen on peripheral blood smear. ADAMTS 13 activity was mildly decreased at 38%. TTP diagnosis was made. She received 5 plasmapheresis rounds and she responded very well. Patient renal function was improved after the first round of plasmapheresis. Laboratory work up showed positive ANA and dsDNA with low complement level. Diagnosis of SLE was made. Patient was treated with Prednisone. Patient did very well and she was discharged home on Prednisone in a good condition. DISCUSSION: TTP is a disease of a broader spectrum diseases of Thrombotic Microangiopathy. TTP is defined by hemolysis, renal impairment, Microangiopathy hemolytic anemia, fever, and neurologic symptoms which all exist only in 5% of cases. ADAMTS 13 activity level is a helpful measurement to approach the diagnosis, but mild impairment of ADAMTS 13 level does not` exclude severe TTP. Acquired TTP incidence based on the Oklahoma TTP-HUS registry is three per one million case a year, 1-4% of these cases are related to SLE. SLE usually more common in Asians and African American females between 16-55 years of age and it is extremely rare in older than 65 years. CONCLUSIONS: • Connective tissue diseases should always be considered in the differential diagnosis when a patient presents with TTP • ADAMTS 13 activity is a helpful test for TTP diagnosis, but not always correlate with the severity of the disease Reference #1: 4. Reese JA, Muthurajah DS, Kremer Hovinga JA, et al. Children and adults with thrombotic thrombocytopenic purpura associated with severe, acquired Adamts13 deficiency: comparison of incidence, demographic and clinical features. Pediatr Blood Cancer 2013; 60:1676. Reference #2: 2. Pons-Estel GJ, Alarcón GS, Scofield L, et al. Understanding the epidemiology and progression of systemic lupus erythematosus. Semin Arthritis Rheum 2010; 39:257. Reference #3: 7. Froissart A, Buffet M, Veyradier A, et al. Efficacy and safety of first-line rituximab in severe, acquired thrombotic thrombocytopenic purpura with a suboptimal response to plasma exchange. Experience of the French Thrombotic Microangiopathies Reference Center. Crit Care Med 2012; 40:104. DISCLOSURES: No relevant relationships by Muhammad Farhan Khaliq, source=Web Response no disclosure on file for Hesham Mohamed; No relevant relationships by Dany Tager, source=Web Response

Efficacy of eculizumab in severe ADAMTS13-deficient thrombotic thrombocytopenic purpura (TTP) refractory to standard therapies

Thrombotic thrombocytopenic purpura (TTP) is a rare microangiopathic hemolytic anemia (MAHA) defined by mechanical hemolytic anemia, severe thrombocytopenia, and systemic visceral ischemia due to systemic platelet-rich microthrombi. Forty percent of patients with autoimmune TTP experience one or multiple relapses. Patients with refractory TTP are currently managed by corticosteroids, twice-daily PEX, and the anti-CD20 monoclonal antibody rituximab. Herein, we report two cases of severe TTP, refractory to those standard agents. On the basis of the fact that in cases of severe TTP the classical complement pathway is activated, and that the alternative pathway is also involved, both patients underwent eculizumab (anti-C5 monoclonal antibody) therapy. We observed prompt hematological and organ system responses to the eculizumab and the recovery of plasma ADAMTS-13 activity in both cases. Moreover, the fact that both patients discontinued eculizumab, maintaining the response, emphasizes the possibility of its usefulness for limited treatment periods. In conclusion, the diagnostic and therapeutic algorithm in TTP appears complicated by increasing evidence of complement involvement and the eculizumab seems to be a potential agent for refractory patients.

Thrombotic thrombocytopenic purpura (TPP) successfully rescued by plasma exchange in the ICU: A report of two cases.

Thrombotic thrombocytopenic purpura (TTP) is a rare, life-threatening disorder, which is characterized by thrombus formation in small blood vessels. The present study retrospectively analyzed the clinical data from two patients with severe TTP, who were treated successfully in the intensive care unit (ICU) at the Liaocheng People's Hospital in 2013. Comprehensive therapies were administered to the patients, including plasma exchange (PE), mechanical ventilation (case 1 only), steroid therapy, blood transfusion and anti-inflammatory treatment (case 2 only). The two patients returned to a stable state and were transferred back to the hematology department following PE. The positive outcome achieved for these patients suggests that early intervention involving bedside PE in the ICU may reduce the mortality rate of patients with severe TTP who have concurrent respiratory or circulatory failure and cannot be treated in the dialysis unit.

Twice-daily therapeutical plasma exchange-based salvage therapy in severe autoimmune thrombotic thrombocytopenic purpura: the French TMA Reference Center experience.

Daily therapeutic plasma exchange (TPE) and rituximab improved thrombotic thrombocytopenic purpura (TTP) prognosis. In the more severe cases, salvage therapies including twice-daily TPE and/or cyclophosphamide may be proposed and require evaluation. TTP was defined as a thrombotic microangiopathy (TMA) with severe (<10%) acquired ADAMTS13 deficiency. Among patients included in the French Reference Center for TMA registry, we considered those with a severe disease (i.e., unresponsive to daily TPE and rituximab) who received twice-daily TPE. Nineteen of 289 (6.6%) patients with TTP were treated by twice-daily TPE between 2008 and 2014. Twice-daily TPE was associated with rituximab in 16 cases. The median duration of twice-daily TPE treatment was 3d (2-22d). In 6 patients (31.6%), additional treatments (mainly pulses of cyclophosphamide) were performed because of a persistently refractory disease (4 cases) or an exacerbation (2 cases), despite twice-daily TPE. Only one patient (5.3%) died. The other 18 achieved a durable complete remission 25.5d (13-68d) after the first TPE. The median follow-up was 14.4months (7d-45months). Twice-daily TPE may be an efficient strategy in the more severe TTP patients with a short-term life-threatening disease that could overcome their poor prognosis.

Splenectomy and/or cyclophosphamide as salvage therapies in thrombotic thrombocytopenic purpura: the French TMA Reference Center experience

The objective was to assess the efficacy and safety of splenectomy and cyclophosphamide as salvage therapies in severe thrombotic thrombocytopenic purpura (TTP). During a 10-year period, patients who did not improve with plasma exchanges, steroids, vincristine, and/or rituximab were considered for splenectomy or cyclophosphamide. Patients with a documented severe (<10% of normal value) acquired ADAMTS13 deficiency are reported here. Eighteen patients with a severe acquired ADAMTS13 deficiency required a salvage therapy. Thirteen patients had a splenectomy 19 (interquartile range [IQR], 10-51) days after TTP diagnosis. One patient died the day after splenectomy. The remaining patients improved platelets (PLTs) until Day 6, along with a rapid and major lactate dehydrogenase improvement. Six patients, however, subsequently experienced a transient worsening. Durable PLT count recovery in survivors was observed within 13 (IQR, 11.5-25.5) days. Postoperative complications included thromboembolic events (two cases) and infections (five cases). Five patients received pulses of cyclophosphamide 12 (IQR, 12-15) days after TTP diagnosis. All patients recovered PLTs 10 (IQR, 9-24) days after the first pulse and two experienced a transient worsening. Three patients experienced infections. Three relapses occurred 5 months, 2.5 years, and 4.5 years after splenectomy and one relapse occurred 3.5 years after cyclophosphamide. After a 2.5 (IQR, 0.75-6.2)-year follow-up, the overall survival was 94%. Cyclophosphamide and splenectomy provide comparable high remission rates in severe TTP with acceptable side effects and should be considered in the more severe patients who do not improve with other therapies.

Targeting B cells in severe thrombotic thrombocytopenic purpura–a road to cure?*

Targeting B cells in severe thrombotic thrombocytopenic purpura–a road to cure?*

A Case of Severe Thrombotic Thrombocytopenic Purpura With Concomitant Legionella Pneumonia: Review of Pathogenesis and Treatment

Thrombotic thrombocytopenia purpura (TTP) is a severe multisystem disorder characterized by fever, microangiopathic hemolytic anemia, thrombocytopenia, neurologic symptoms, and impaired renal function. Platelet counts are usually diminished, whereas the bone marrow shows a large number of megakaryocytes indicating peripheral destruction and consumption of platelets. Coagulation studies in patients with TTP are normal or slightly elevated, which helps differentiate this entity from disseminated intravascular coagulation. The peripheral smear shows an abundance of schistocytes, reticulocytes, and, at times, nucleated red blood cells. Serum lactate dehydrogenase and indirect bilirubin are elevated as a result of mechanical destruction of red blood cells. Legionella pneumophila has been identified as a relatively common cause of both community-acquired and hospital-acquired pneumonia. An association between Legionella and TTP has only been cited once in the literature. Here we present a case of severe TTP with concurrent Legionella infection. Our patient presented with the classic clinical findings of TTP and an ADAMTS13 level of less than 5% associated with an inhibitor. After a 3-week treatment course with plasma exchange, steroids, and antibiotics, he had complete clinical recovery and his ADAMTS13 level increased to greater than 75%.

Schwerste thrombotisch-thrombozytopenische Purpura (TTP) nach H1N1-Vakzinierung

Thrombotic thrombocytopenic purpura (TTP) is a severe disease with microthrombi in various organs. The idopathic subtype is characterized by reduced ADAMTS13 activity mediated via autoantibodies against this protease. Induction of autoantibodies mechanistically is incompletely understood, but certain drugs can induce anti-ADAMTS13 antibodies through hapten mechanisms. A 56-year-old man was admitted from an external hospital because of a rapidly worsening general condition, hemolytic anemia (hemoglobin 4.17 mmol/l, hematocrit 0.19), and thrombocytopenia (22 Gpt/l) for unknown reasons. Additionally, he was found to have an elevated lactate dehydrogenase (45.37 μmol/l/s). 13 days before hospitalization he had received vaccination against H1N1. Laboratory tests revealed an increased total bilirubin (126 μmol/l), and a decreased haptoglobin level (< 0.08 g/l). The blood smear showed 24% fragmentocytes. Direct and indirect Coombs test were negative. TPP was diagnosed based on the clinical presentation and the detection of ADAMTS13 antibodies. Despite daily plasma exchange via plasmapheresis and administration of corticosteroids, there was no significant rise in platelet counts. Immunosuppression with a total of four weekly doses of rituximab (375 mg/m(2) body surface area) was added. Over the next 5 weeks, the platelet count very slowly rose. After a total of 46 sessions, plasmapheresis was ended with complete remission of the disease. This report emphasizes the immunologic susceptibility of TTP, and suggests the potential, but not proven role of H1N1 vaccination in the pathogenesis of TTP, because no serum before vaccination was available. Severe autoantibody TTP can be successfully treated by administering rituximab in addition to standard treatment with plasmapheresis and corticosteroids.

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.

Association of Treatment with Sirolimus (SIR) and Calcineurin Inhibitor (CNI) for Prevention or Treatment of Graft-Vs-Host Disease (GVHD) with Transplant Associated Microangiopathy (TAM).

Sirolimus (SIR), an inhibitor of mammalian target of rapamycin (mTOR), is an immunosuppressive agent that is synergistic with CNI to prevent or treat GVHD in patients (pts) undergoing allo-HST (Cutler, Biol Blood Marrow Transplant . 2004; 10:328). Transplant associated microangiopathy (TAM) is a multi-factorial complication of allo- HST, associated with CNI. Recently, the addition of SIR to CNIs was reported to result in a higher than expected (10.8%) incidence of TAM (Cutler et al. Biol Blood Marrow Transplant . 2005; 11:551). We analyzed the incidence and clinical characteristics of TAM in 2 groups of pediatric patients (pts): the prevention group (GP): pts who received SIR and tacrolimus (TAC) for prevention; and the treatment group (TG): pts treated with SIR and a CNI (TAC or cyclosporine) for exacerbation of GVHD.Methods: A retrospective chart review of pts with allo-HST who received SIR/TAC for either prevention or treatment of GVHD. Demographic data, clinical course, occurrence of GVHD and TAC and SIR levels were recorded. TAM was defined as serum creatinine (SCr) of ≥ 50% above baseline, elevated LDH levels (>X2 upper limit of normal), presence of schistocytes or persistence of nucleated red blood cells, and prolonged or progressive thrombocytopenia. For PG the risk period was defined between days −1 to +60 of HSC. The risk period for the TG was defined from the first day of SIR/TAC until day +30 after the last dose was given.Results: Records of 45 pts who were treated with SIR/TAC were reviewed. The median age of 21 patients in PG was 9.1 yr (2.9–22); male gender, n=13. The median age in 24 TG pts was14.7 yr (3.3–20.6); male gender, n= 11. Conditioning regimens consisted of TBI based regimens (64%), or chemotherapy only (36%). Diagnoses included ALL (40%), AML (27 %), NHL (9%), Fanconi's (4 %), and other (9%). The median follow up for the surviving patients is 28.6 months. TAM criteria were met in 15 ( 30%) patients who received SIR/TAC, 5 PG pts (23.8%) and 10 TG pts ( 41.6%). Two PG patients died from multi-organ failure (MOF) related to other reasons (VOD, n=1 and multi-organism infection, n=1). Both pts had hemolytic uremic syndrome (HUS), possibly contributing to MOF. One patient developed seizures secondary to thrombotic thrombocytopenic purpura (TTP) as a complication of TAM. TAC and SIR levels were within the desired range (WDR, (≤10 ng/ml, for each) in this patient and signs and symptoms of TAM and TTP resolved after discontinuation of both TAC and SIR. In 2 patients TAM findings were asymptomatic, without progression to HUS or TTP. SIR/TAC levels in these patients were all WDR. Among 10 TG pts that met TAM criteria, 2 pts progressed to HUS and one developed severe TTP. All 3 patients with complicated TAM died (HUS, n=1, MOF, n=1, and idiopathic pneumonitis, n=1). Two of the pts with laboratory, but not clinically apparent TAM died (invasive fungal infection, n=1, IP n=1). In all TG pts with TAM either TAC (n=7) or SIR (n=6) levels exceeded WDR. To identify possible risk factors for TAM, the following parameters were analyzed: age, conditioning regimen, disease type, degree of HLA match. In the PG, only organ failure or high-grade GVHD could be identified as risk factors. In the TG, TAC or SIR levels exceeding WDR, in addition to ac GVHD or chronic GVHD present in all patients, were associated with an increased risk for clinical significant TAM.Conclusion: Organ damage, either by acute GVHD or from other reasons may contribute to development of clinically significant TAM in pts undergoing allo-HST treated with SIR plus CNI. Monitoring TAC or SIR levels and early diagnosis of TAM may prove to be critical in patients with progressive organ damage of GVHD.

Thrombotic thrombocytopenic purpura in the first trimester and successful pregnancy

Dear Editor, Thrombotic thrombocytopenic purpura (TTP) is a rare complication of pregnancy with a poor prognosis and a high fetal mortality when presenting early during gestation. Few cases of TTP (10%) occur during the first trimester [1, 2], the majority occurring at the time of delivery or during post-partum period [4, 6]. Until the effectiveness of plasma infusion and plasma exchange was recognized, TTP was associated with a mortality rate of 95% and, in case of pregnancy-related TTP, the maternal survival was rare and the fetal mortality rate approached 80% [9]. Fetal death is secondary to placental infarction due to thrombotic occlusion of the decidual arterioles [8]. Currently, plasma infusion and plasmapheresis have improved maternal and fetal survival rates [10]. At present, it is well known that termination of pregnancy is rarely needed and that the fetal survival rate could be improved by effective maternal therapy [14]. When TTP occurs during the first trimester of pregnancy and delivery of a viable infant is not an option, plasma exchange treatment is urgently indicated and may allow the pregnancy to continue [13]. There are some reports showing that prolonged courses of plasma exchange, beginning as early as 6 weeks of gestation, may achieve and maintain a remission of TTP allowing delivery of a healthy, full-term infant [1]. When plasma exchange fails to induce remission, therapeutic abortion may be considered, although the response of TTP to termination of pregnancy is uncertain. We have previously reported a case of a successful pregnancy in a young female who developed a severe TTP relapse at 18 weeks of gestation [5]. In the present study, we describe a case of a first pregnancy concomitant to a severe TTP diagnosed in the first trimester with maternal survival and delivery of a healthy child. In August 2004, a 26-year-old nulliparous woman at 9 weeks of gestation presenting macrohematuria and ecchymoses was admitted to our institution. Laboratory data showed thrombotic microangiopathy, with anemia (7.5 g/dl), thrombocytopenia (platelets 6×10/l), numerous schistocytes (60%) in the peripheral blood smears, elevated levels of lactic dehydrogenase (1,472 IU/l range 70–190) and bilirubin (total 3.4 mg/dl, normal value 0.4–1.1, indirect 3 mg/dl, normal value 0.1–0.4), reticulocytosis (250×10/l), and negative direct/indirect Coombs’ test. Renal function was normal. Bone marrow aspirate showed a normal bone marrow cytomorphology. Thrombophilic screening showed normal levels of antithrombin (AT), absence of lupus anticoagulant (LAC), normal levels of C and S proteins, and no mutations of Leiden Factor V and prothrombin gene, while a heterozygous mutation of MTHFR C677T, with normal plasma homocysteine concentrations, was found. Serologic examinations were negative for anti-extractable nuclear antibodies and anticardiolipin antibodies. Unfortunately, ADAMTS-13 levels and inhibitor were not determined during the acute event. On the basis of the symptoms and laboratory tests, a clinical diagnosis of TTP was made and the patient was treated with intravenous methylprednisolone (2 mg/kg/die to 120 mg/die) and daily plasmapheresis, with plasma replacement of 30 ml/kg/die, in combination with continuous infusion of fresh frozen plasma (FFP) (10 ml/kg/die). Folic acid (15 mg/die) support was given. The initial response was Ann Hematol (2009) 88:287–289 DOI 10.1007/s00277-008-0579-4

Quantification of ADAMTS-13 Activity and Antigen from the Same Sample by a Newly Developed Combi-Actibind Assay (TECHNOZYM® ADAMTS-13).

Defects in activity and/or antigen levels of ADAMTS-13, the von Willebrand Factor (vWF) cleaving protease, are viewed as the main cause inducing the microvascular thrombotic disorder TTP (thrombotic thrombocytopenic purpura) that is in more than 90% of cases fatal if not treated early and appropriately. Malfunction of ADAMTS-13 with respect to cleave multimeric vWF can be caused by auto-antibodies directed against ADAMTS-13, by decreased presence of ADAMTS-13 in the circulation or by defective activity of ADAMTS-13. Therefore rapid and reliable diagnosis of ADAMTS-13 parameters is a clinical need. We present here a new assay for quantification of ADAMTS-13 activity and antigen levels based on ELISA format and thus suitable for fast and routine measurements.The method is based on the Actibind® technology, using a monoclonal antibody to capture ADAMTS-13 from plasma to a microtiter plate. Activity is then assayed by a fluorescent substrate. After removal of the substrate solution, antigen can be assayed by standard ELISA technology using a polyclonal antibody followed by a peroxidase labelled secondary antibody. Thus both parameters can be measured from the same sample consequently in the same assay allowing calculation of specific activities of ADAMTS-13.Dilutions of normal plasma (pool of 100 normal donors) were used as calibrators. The standard curve for the activity assay comprises a range from 3.7% to 100 % of normal plasma activity, thus samples of severe TTP (definition: activity below 5%) can be detected with sufficient sensitivity. 42 samples from TTP patients were tested in this new activity/antigen assay as well as in the TECHNOZYM ADAMTS-13 INH assay that allows determination of anti ADAMTS-13 auto antibodies. Using these two assays a significant negative correlation was found between ADAMTS-13 activity and the presence of autoantibodies, 82% of the samples with extremely low ADAMTS-13 activity (<5%) had high levels of autoantibodies. A less stringent positive correlation was found between ADAMTS-13 antigen and ADAMTS-13 activity. Out of 30 samples with low ADAMTS-13 activity (< 25%) 15 samples had antigen levels less than 50% of normal. Out of the 42 samples from TTP patients, 3 samples were found without auto antibodies but still low activity. 2 of these samples also had low antigen levels. Moreover, the TTP samples had significantly higher levels of vWF:CBA activity (p<0.05) consistent with the presence of high molecular weight vWF.This combined new assay clearly adds to the diagnostic possibilities to differentiate patients with TTP with respect to defects in ADAMTS-13 function and antigen concentration. In addition, the results of this assay correlate with the clinical picture and the decreased functional activity of ADAMTS-13 leading to increased levels of vWF multimers and in turn platelet consumption.

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.

Severe thrombotic thrombocytopenic purpura (TTP) induced or exacerbated by the immunostimulatory herbEchinacea

American Journal of HematologyVolume 81, Issue 3 p. 224-224 Letters and CorrespondenceFree Access Severe thrombotic thrombocytopenic purpura (TTP) induced or exacerbated by the immunostimulatory herb Echinacea Liatsos George, Liatsos George Department of Internal Medicine, Hippokration Hospital, Athens, GreeceSearch for more papers by this authorElefsiniotis Ioannis, Elefsiniotis Ioannis Department of Internal Medicine, Hippokration Hospital, Athens, GreeceSearch for more papers by this authorTodorova Radostina, Todorova Radostina Department of Internal Medicine, Hippokration Hospital, Athens, GreeceSearch for more papers by this authorMoulakakis Antonios, Moulakakis Antonios Department of Internal Medicine, Hippokration Hospital, Athens, GreeceSearch for more papers by this author Liatsos George, Liatsos George Department of Internal Medicine, Hippokration Hospital, Athens, GreeceSearch for more papers by this authorElefsiniotis Ioannis, Elefsiniotis Ioannis Department of Internal Medicine, Hippokration Hospital, Athens, GreeceSearch for more papers by this authorTodorova Radostina, Todorova Radostina Department of Internal Medicine, Hippokration Hospital, Athens, GreeceSearch for more papers by this authorMoulakakis Antonios, Moulakakis Antonios Department of Internal Medicine, Hippokration Hospital, Athens, GreeceSearch for more papers by this author First published: 21 February 2006 https://doi.org/10.1002/ajh.20531Citations: 4AboutPDF ToolsRequest permissionExport citationAdd to favoritesTrack citation ShareShare Give accessShare full text accessShare full-text accessPlease review our Terms and Conditions of Use and check box below to share full-text version of article.I have read and accept the Wiley Online Library Terms and Conditions of UseShareable LinkUse the link below to share a full-text version of this article with your friends and colleagues. Learn more.Copy URL Share a linkShare onFacebookTwitterLinkedInRedditWechat REFERENCES 1Gertsch J, Schoop R, Kuenzle U, Suter A. Echinacea alkylamides modulate TNF-alpha gene expression via cannabinoid receptor CB2 and multiple signal transduction pathways. FEBS Lett 2004; 577(3): 563– 569. 2Bielory L. Complementary and alternative interventions in asthma, allergy and immunology. Ann Allergy Asthma Immunol 2004; 93(2 Suppl 1): S45– S54. 3Mishima S, Saito K, Maruyama H, et al. Antioxidant and immuno-enhancing effects of Echinacea purpurea. Biol Pharm Bull 2004; 27(7): 1004– 1009. 4Randolph RK, Gellenbeck K, Stonebrook K, et al. Regulation of human immune gene expression as influenced by a commercial blended Echinacea product: preliminary studies. Exp Biol Med (Maywood) 2003; 228(9): 1051– 1056. 5Lee AN, Werth VP. Activation of autoimmunity following use of immunostimulatory herbal supplements. Arch Dermatol 2004; 140(6): 724– 727. Citing Literature Volume81, Issue3March 2006Pages 224-224 ReferencesRelatedInformation

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

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