Secondary Thrombotic Thrombocytopenic Purpura Research Articles

Analysis of Prognosis and Therapeutic Effect of Patients with Thrombotic Thrombocytopenic Purpura

To summarize the features of clinical and laboratory parameters of thrombotic thrombocytopenic purpura (TTP), and to analyze the factors affecting the prognosis and therapeutic effect during the acute phase of the disease. The etiology, clinical features, laboratory parameters, treatment regimens and other data of 59 TTP patients admitted to Hunan Provincial People's Hospital were retrospectively analyzed. And the differences of each variable between the death group and the survival group were compared, the correlations between each variable and prognosis, as well as the therapeutic effect of the acute phase patients were analyzed. Among the 59 cases of TTP, one 4-year-old boy was inherited TTP, the other 58 cases were acquired TTP (39 cases were idiopathic TTP and 19 were secondary TTP), including 27 males and 31 females, with a median age of 54 (11-84) years old. 36 patients were tested for von Willebrand factor cleaving protease (ADAMTS13) activity, and 34 patients (94.44%) had decreased ADAMTS13 activity. There was a statistical difference in the activity of ADAMTS13 between idiopathic and secondary TTP patients (P<0.001). There were statistical differences in factors such as age (64 vs 51 years), ALT/AST ratio (0.61 vs 0.36), therapeutic plasma exchange (TPE) times (3 times vs 8 times), and TPE duration (3 d vs 9 d) between the death and survival groups. Multivariate analysis showed that total times of TPE (OR=5.175,95%CI: 1.169-22.914, P=0.030), ALT/AST ratio (OR=4.387, 95%CI: 1.019-18.891, P=0.047) were associated with mortality. COX regression analysis showed that degree of neuropsychiatric disorder (HR=0.200, 95%CI: 0.084-0.474, P<0.001), days from onset to initiation of TPE (HR=0.288, 95%CI: 0.114-0.726, P=0.008), treatment regimen (HR=0.336, 95%CI: 0.125-0.902, P=0.030) were associated with platelet recovery and therapeutic effect in the acute phase of the patients. TTP patients with high ALT/AST ratio have a higher mortality rate. Patients with enough times and full course of TPE have lower mortality rate. Poor therapeutic effect were found in TTP patients with severe neuropsychiatric disorders, delayed diagnosis and treatment, and who added rituximab when TPE was ineffective.

Thrombotic Thrombocytopenic Purpura with Mixed Connective Tissue Disease –Non-immune Hemolytic Anemia with Autoimmune Disease - Rare Case Report

TTP (Thrombotic Thrombocytopenic purpura) is a nonimmune, microangiopathic hemolytic anemia (MAHA), associated with thrombocytopenia, fever, neurologic or renal dysfunction. Mixed connective tissue disease (MCTD) is not a specific disorder and identified serologically by high titers of of antibodies to RNP. Coexistence of TTP with asymptomatic MCTD is rare encounter. We describe here a rare case of secondary TTP in a 42 year, old female presenting as menorrhagia for seven days, severe headache and one episode of seizure. This case emphasizes the early diagnosis of TTP and its association with underlying condition for proper management and to avoid fatal outcome. KeyWords: Microangiopathic hemolytic anemia (MAHA); Thrombotic Thrombocytopenic purpura( TTP); hemolytic uremic syndrome(HUS); Mixed connective tissue disease(MCTD); U1-Ribonucleoprotein (RNP); Antineuclear antibody(ANA); A disintegrin and metalloproteinase with a thrombospondin type 1 motif,member 13(ADAMTS 13)&#x0D; J Bangladesh Coll Phys Surg 2020; 38(1): 46-48

Recombinant thrombomodulin for secondary thrombotic thrombocytopenic purpura.

In the pathogenesis of thrombotic thrombocytopenic purpura (TTP), reductions in the enzyme activity of ADAMTS13, which cuts ultralarge von Willebrand multimers, generates shear stress on the microvascular endothelium, leading to platelet aggregation and the formation of a thrombus. ADAMTS13 activity is markedly decreased in typical TTP, but is only mildly reduced in secondary TTP, which concomitantly develops with primary disease. The latter develops with septic disseminated intravascular coagulation (DIC) and often causes organ failure. Recombinant thrombomodulin (rTM) is a drug that is used to treat DIC and may also remit TTP because it improves vascular endothelial dysfunction. Therefore, we herein investigated the efficacy of rTM in patients treated for the pathology of secondary TTP. Patients who were admitted to the Emergency and Critical Care Center of our hospital and met the following conditions were extracted and retrospectively analyzed: hemolytic anemia accompanied by fragmented red blood cells (Hb < 12 g/dL or lower); thrombocytopenia (<100 × 103/μL); and ADAMTS13 activity <50%. Sixteen patients were included and accompanied by Kidney Disease: Improving Global Outcomes (KDIGO) stage 2 or more severe nephropathy and DIC. Eleven and 5 patients treated with and without rTM (the rTM and non-rTM treatment groups, respectively) were compared, and no significant difference was noted in their basic characteristics, such as background disease and severity. No significant difference was observed in survival rates; however, the platelet count, which is an important outcome of treatments for TTP, significantly increased in the rTM treatment group: 3.3 ± 2.6→11.3 ± 14.6 versus 3.5 ± 3.7→5.7 ± 3.9 (×1000/μL) (P = 0.034). Thrombotic thrombocytopenic purpura originally requires invasive treatments and its prognosis is not favorable. Blood thrombomodulin levels also markedly increase due to vascular endothelial dysfunction, whereas rTM alleviates vascular endothelial dysfunction in TTP patients with high blood TM levels, suggesting the importance of administering rTM. Thus, rTM may be effective for secondary TTP and may be adopted as adjuvant therapy.

Primary and Secondary Thrombotic Microangiopathy Referred to a Single Plasma Exchange Center for Suspected Thrombotic Thrombocytopenic Purpura: 2000-2011

Background: Patients who present with unexplained thrombocytopenia, that is, hemolytic anemia with end-organ dysfunction with a normal coagulation profile are suspected to have thrombotic thrombocytopenic purpura (TTP) and are usually referred to a plasma exchange (PE) center for immediate treatment to prevent mortality. Here, we describe the distribution and outcomes of patients with suspected TTP referred to a single center for PE therapy. Methods: In this retrospective cohort study, we reviewed the data of all consecutive patients who were treated with PE for suspected TTP at our center between January 2000 and December 2011 (Canada). Patients were followed for a median of 73 months. Results: Of 137 patients, 70 (51%) were determined to have primary (idiopathic) TTP and 67 (49%) secondary TTP or hemolytic uremic syndrome (HUS). Patients with primary TTP were twice as likely to be refractory than those with secondary TTP or HUS: 27 vs. 12%; p = 0.03. Patients with primary TTP were more likely to experience remission (61/70 (87%) vs. 45/67 (67%); p = 0.01); however, the relapse rate was higher in patients with primary versus secondary TTP-HUS: 11 vs. 1.5%, respectively (p = 0.03). The overall mortality rate was 23% (13 vs. 33% in those with primary vs. secondary TTP-HUS; p = 0.007). After excluding deaths from scleroderma renal crisis (100% mortality), malignancy (75% mortality) and stem cell transplant (50% mortality), the survival rate for secondary TTP was 85%. Conclusions: In contrast to patients with secondary TTP or HUS, those with primary TTP have a higher refractory and relapse rate, but are also more likely to achieve remission and survive.

Interferon-α is not elevated in idiopathic thrombotic thrombocytopenic purpura patients.

Idiopathic thrombotic thrombocytopenic purpura (TTP) patients have ADAMTS13 deficiency, which is usually caused by ADAMTS13 autoantibodies. However, the triggering factors for the autoantibody production remain unclear. Interferon-α (IFN-α) is a cytokine involved with many autoimmune processes such as inducing the activation of peripheral dendritic cells and stimulating T cells and B cells. It also plays an important role in some autoimmune diseases. Elevated IFN-α levels have been observed in some TTP patients and previous case reports have shown the occurrence of TTP after IFN-α treatment. Thus, we hypothesized that high levels of IFN-α would correlate with presence of ADAMTS13 autoantibodies. However, we did not observe elevated IFN-α levels in 36 TTP patients (mean 5.29 pg/ml, standard deviation (SD) 26.56 pg/ml) compared to healthy controls (mean 0 pg/ml, SD 0 pg/ml), P = 0.59. IFN-α levels of most patients (94%) were undetectable. Only two patients had increased IFN-α levels and ADAMTS13 autoantibodies were detected in these two patients. Interestingly, both the patients had an underlying autoimmune disease. Although there have been cases of secondary TTP following IFN-α treatment, no evidence supports a role of IFN-α in the development of idiopathic TTP in our patient population.

Postoperative thrombotic thrombocytopenic purpura

Thrombotic thrombocytopenic purpura (TTP) is a rare, life-threatening disease characterized by acute episodes of thrombocytopenia and microangiopathic hemolytic anemia occurring due to platelet and von Willebrand factor deposition and hyaline thrombi formation in arterioles and capillaries throughout the body, which results in organ ischemia. TTP can be idiopathic or secondary, and there are several causes of secondary TTP. There is a clinical syndrome resembling TTP that occurs after surgical procedures, so-called "postoperative TTP" (pTTP). In this review, the differential diagnosis, pathogenesis and clinical and laboratory features of pTTP, together with the treatment modalities and outcomes of the patients, are discussed. The pTTP is a diagnosis of exclusion, and disseminated intravascular coagulation, heparin-induced thrombocytopenia and medication-induced effects should be ruled out. As in classical TTP, patients with pTTP should be diagnosed and treated with therapeutic plasma exchange (TPE) as early as possible to reduce their morbidity and mortality. Although rarely seen, surgeons and physicians of all specialties should be alert to the possibility of pTTP, and since pTTP is a life-threatening event that usually can be treated successfully with TPE, especially when diagnosed early in its course, it is critical to recognize and treat pTTP promptly.

Detectable Or Normal ADAMTS13 Activity In Patients Presenting With Thrombotic Thrombocytopenic Purpura (TTP) Is Associated With Poor Renal Outcomes

Background and Objective Thrombotic thrombocytopenic purpura is often associated with a severe congenital or antibody mediated deficiency of ADAMTS13. The wider availability of the ADAMTS13 activity assay has led to it being used to aid in making treatment decisions. However, a proportion of patients with clinically diagnosed TTP who respond well to plasma exchange do not have severe ADAMTS13 deficiency. We studied a cohort of 57 patients with TTP to compare the presenting features and clinical outcomes of patients with and without severe ADAMTS13 deficiency. Methods We identified a cohort of 57 patients treated for TTP at the Cleveland Clinic between 2000 and 2012 who underwent testing for ADAMTS13 activity prior to transfusion of blood products or initiation of plasma exchange. Clinical and laboratory data were gathered from their medical records. Fisher exact test was used to compare categorical variables and the T-test was used to compare continuous variables between patients with and without severe ADAMTS13 deficiency defined as undetectable (&lt;5%) activity. Results Thirty six (63%) of 57 patients had severe ADAMTS13 deficiency while the remaining 21 (37%) has ADAMTS13 activity ranging from 8% to 56%. Of the 36 patients with severe ADAMTS13 deficiency, 28 had idiopathic TTP while 8 had secondary TTP. For patients with detectable ADAMTS13 levels there were 12 and 9 patients with idiopathic and secondary TTP respectively. There was no significant difference in the clinical setting (idiopathic versus secondary TTP) (p=100), age (p=0.190) or sex distribution (p=0.362) between patients with and without severe ADAMTS13 deficiency. Patients with and without severe ADAMTS13 deficiency had heterogeneous clinical presentations which were not significantly different with comparable rates of fever (p=0.555), neurological symptoms (p=0.140), anemia (p=0.203) and thrombocytopenia (0.223). However, patients with detectable ADAMTS13 activity had higher rates of renal impairment at presentation (34% versus 72%, p=0.012) and higher mean serum creatinine at presentation (3.23±2.55 versus 1.94±2.21, p=0.009). Both groups of patients had similar rates of response to plasma exchange, mortality (p=0.620) and relapse (p=1.000). However patients with detectable ADAMTS13 activity had significantly worse renal outcomes than patients with severe deficiency with higher rates of acute renal failure needing dialysis [Relative Risk (RR) 2.89, 95% CI 1.66-5.05), progression to chronic renal insufficiency (RR 2.86, 95% CI 1.37-5.96) and end stage renal disease needing dialysis (RR 3.12, 95% CI 2.11-4.61). Conclusions Patients with and without severe ADAMTS13 deficiency have similar presenting features and clinical outcomes (mortality and relapse). Patients with detectable or normal ADAMTS13 activity have worse renal outcomes (acute renal failure, chronic renal insufficiency). At least some of these patients may have an alternative form of thrombotic microangiopathy such as atypical hemolytic uremic syndrome (aHUS) and may be candidates for earlier evaluation for aHUS and possible complement directed therapy. Disclosures: No relevant conflicts of interest to declare.

Response to "Predictors of survival in thrombotic thrombocytopenic purpura" Haematologica 2013;98(5):e58

The French TMA Reference Center recently described in this Journal a predictive model for death in patients with idiopathic acquired thrombotic thrombocytopenic purpura (TTP).1 In their paper, Chaturvedi and Bhatia claimed that our model may not be applicable to the majority of patients with TTP because we only considered patients with severe ADAMTS13 deficiency.2 These authors suggest that all patients with an apparent diagnosis of idiopathic or secondary TTP should have been analyzed, irrespective of ADAMTS13 activity. We disagree with this view. Indeed, the association of a microangiopathic hemolytic anemia with peripheral thrombocytopenia and organ failure are not specific to TTP. Rather, these features define a heterogeneous group of disorders that have overlapping clinical manifestations and are grouped under the broader term of thrombotic microangiopathy (TMA), which includes not only TTP, but also other distinct diseases, such as the hemolytic and uremic syndrome (HUS), and TMA associated with various conditions (i.e. cancer, allogeneic hematopoietic stem cell transplantation, chemotherapy, human immunodeficiency virus infection, etc.). All these diseases have now been clearly characterized as having specific features in terms of pathophysiology, prognosis and treatment, and, therefore, cannot be considered as a single disease. TMA syndromes are currently classified on the basis of their pathophysiological mechanisms.3,4 This new molecular classification is more adapted to the increasing use of targeted therapies, such as B-cell depleting therapies (rituximab; Mabthera®, Roche) for acquired TTP and complement blockers (eculizumab; Soliris®, Alexion) for atypical HUS.5–7 Moreover, Chaturvedi and Bhatia wrongly consider TTP and TTP-HUS to be the same entity. The term TTP-HUS was used by some authors to group TTP and HUS together in their studies, due to the absence of explicit criteria to distinguish between the diseases on the basis of their clinical presentation and standard biology.8 However, TTP-HUS includes distinct diseases, as reflected by the variable frequency (33–75%) of severe ADAMTS13 deficiency in this group of patients.8–10 Conversely, 75–100% of patients diagnosed with TTP on the basis of mild renal involvement display severe ADAMTS13 deficiency, whereas most patients with severe renal failure, and considered, therefore, as having features of HUS, have detectable ADAMTS13 activity.9,11 Likewise, the distinction of idiopathic TMA on the basis of ADAMTS13 activity (severe deficiency and detectable enzyme activity) closely matches the diagnoses of TTP and HUS, respectively.10,12–15 Clearly, TMA can no longer be considered as a single disease in the era of molecular diagnosis and targeted therapies. Accordingly, the aim of our work was to identify original prognostic factors in a specific and homogeneous subset of patients with TMA (i.e. acquired idiopathic TTP) who were identified accurately on the basis of severe ADAMTS13 deficiency and for whom targeted therapies are available.6 In conclusion, the comment by Chaturvedi and Bhatia revives the old issue of the crucial need for the use of a rigorous terminology in the field of TMA that is acknowledged by all national collaborative groups.12 This requires international efforts to define consensual diagnostic criteria, treatment modalities and definitions of treatment response to allow a common language to be developed and international studies and fruitful meta-analyses to be conducted.

Therapeutic plasma exchange in patients with thrombotic thrombocytopenic purpura: A retrospective multicenter study

Thrombotic thrombocytopenic purpura (TTP) is a particular form of thrombotic microangiopathy typically characterized by thrombocytopenia, microangiopathic hemolytic anemia, fever, neurological abnormalities, and renal dysfunction. TTP requires a rapid diagnosis and an adapted management in emergency. Daily sessions of therapeutic plasma exchange (TPE) remain the basis of management of TTP. Also, TTP is a rare disease that is fatal if it is not treated. TPE has resulted in excellent remission and survival rates in TTP patients. AimWe aimed to present our experience in 163 patients with TTP treated with TPE during the past 5years from 10 centers of Turkey. Patients and methodsOne hundered and sixty-three patients with TTP treated with TPE during the past 5years from 10 centers of Turkey were retrospectively evaluated. TPE was carried out 1–1.5times plasma volume. Fresh frozen plasma (FFP) was used as the replacement fluid. TPE was performed daily until normalization of serum lactate dehydrogenase (LDH) and recovery of the platelet count to >150×109/dL. TPE was then slowly tapered. Clinical data, the number of TPE, other given therapy modalities, treatment outcomes, and TPE complications were recorded. ResultsFifty-eight percent (95/163) of the patients were females. The median age of the patients was 42years (range; 16–82). The median age of male patients was significantly higher than female (53 vs. 34years; p<0.001). All patients had thrombocytopenia and microangiopathic hemolytic anemia. At the same time, 82.8% (135/163) of patients had neurological abnormalities, 78.5% (128/163) of patients had renal dysfunction, and 89% (145/163) of patients had fever. Also, 10.4% (17/163) of patients had three of the five criteria, 10.4% (17/163) of patients had four of the five criteria, and 6.1% (10/163) of patients had all of the five criteria. Primary TTP comprised of 85.9% (140/163) of the patients and secondary TTP comprised of 14.1% (23/163) of the patients. Malignancy was the most common cause in secondary TTP. The median number of TPE was 13 (range; 1–80). The number of TPE was significantly higher in complete response (CR) patients (median 15.0 vs. 3.5; p<0.001). CR was achieved in 85.3% (139/163) of the patients. Similar results were achieved with TPE in both primary and secondary TTP (85% vs. 87%, respectively; p=0.806). There was no advantage of TPE+prednisolone compared to TPE alone in terms of CR rates (82.1% vs. 76.7%; p=0.746). CR was not achieved in 14.7% (24/163) of the patients and these patients died of TTP related causes. There were no statistical differences in terms of mortality rate between patients with secondary and primary TTP [15% (21/140) vs. 13% (3/23); p=0.806]. But, we obtained significant statistical differences in terms of mortality rate between patients on TPE alone and TPE+prednisolone [14% (12/86) vs. 3% (2/67), p<0.001]. ConclusionsTPE is an effective treatment for TTP and is associated with high CR rate in both primary and secondary TTP. Thrombocytopenia together with microangiopathic hemolytic anemia is mandatory for the diagnosis of TTP and if these two criteria met in a patient, TPE should be performed immediately.

Clinical experience in treatment of thrombotic thrombocytopenic purpura - hemolytic uremic syndrome with 28 patients

Neither optimal treatment nor significance of ADAMTS13 (A Desintegrin And Metalloprotease with ThromboSpondin type 1 repeats) activity for diagnosis and therapy of thrombotic thrombocytopenic purpura (TTP) and hemolytic-uremic syndrome (HUS) have not been defined yet. The aim of the report is to analyze response to different volumes of plasma exchange (PE), and relationship to ADAMTS13. 28 patients clinically diagnosed with idiopathic TTP (n = 18), secondary TTP (n = 4), atypical HUS (n = 3) and typical HUS (n = 3) manifested 31 acute episodes. Patients were treated with PE in 26, and with plasma transfusion in 5 episodes with additional different therapies. PE volumes were as follows: 1 in 7, 1.5 in 3, 2 in 14, and intensifying schedule (1 to 1.5) in 2 episodes. Procedure number was lower in patients treated with 2 and 1.5 (p = 0.019) than in those treated with 1 volume exchange and PE intensifying, respectively (p = 0.010). PE response rate was 25/26 (96.15%). Exacerbation frequency was higher in idiopathic TTP patients (3/19) treated with 1 compared with patients treated with > 1 volume exchange (p = 0.003). Survival rate was 25/28 (89.29%). ADAMTS13 activity was reduced in 22 with severe deficiency in 14 patients. Patients responded to different treatments regardless of ADAMTS13 activity, requiring less PEs with larger volume exchanges.

Diagnostic relevance of ADAMTS13 activity: Evaluation of 28 patients with thrombotic thrombocytopenic purpura - hemolytic uremic syndrome clinical diagnosis

The significance of ADAMTS13 (a disintegrin and metalloproteinase with thrombospondin motif-13) activity for diagnosis and therapy of thrombotic thrombocytopenic purpura (TTP) and hemolytic uremic syndrome (HUS) is still a controversial issue. The aim of this report was to analyze the value of ADAMTS13 measurements in the diagnosis of TTP and HUS. At presentation, we analyzed patients with idiopathic TTP (n = 18), secondary TTP (n = 4), diarrhea positive HUS (n = 3) and diarrhea negative HUS (n = 3) treated in Belgrade, Serbia from 2004 to 2010. ADAMTS13 activity from acute phase samples was measured using the residual collagen binding activity assay at the Haemophilia and Thrombosis Centre, Milan, Italy. There was a significant correlation between reduced ADAMTS13 activity and idiopathic TTP diagnosis (p = 0.000) as well as between lower ADAMTS13 activities and higher reticulocytes (p = 0.017) and lactate dehydrogenase levels (p = 0.027). Significant correlation was also found between higher protease activity and diagnosis of HUS (p = 0.000). There was a statistically significant correlation between higher ADAMTS13 activities and higher platelets count (p = 0.002), blood urea nitrogen (p = 0.000), and creatinine level (p = 0.000). Severe ADAMTS13 deficiency points at the diagnosis of idiopathic TTP and it is present in the secondary TTP but not in HUS.

Retrospective Analysis of Patients Afflicted with Thrombotic Thrombocytopenic Purpura: A Single Institutional Experience.

AbstractAbstract 2200 Introduction:Thrombotic Thrombocytopenic Purpura (TTP) is an acute life threatening condition characterized by thrombocytopenia, microangiopathic hemolytic anemia, with or without renal failure or neurologic abnormalities, and without another cause for thrombotic microangiopathy. The majority of cases of TTP are associated with a low ADAMTS13 activity which results from antibody to this enzyme. A minority of patients have TTP secondary to congenital deficiency of this enzyme. The mainstay of therapy for TTP is plasmapheresis (PEX) which has increased survival in affected patients from 10% to more than 75%. While TTP is considered as an uncommon disorder, at our institution we suspected that the diagnosis was made more commonly. Therefore we set out to perform a retrospective analysis of cases of TTP to evaluate cases diagnosed over the past 10 years. Methods:We performed a retrospective analysis of all cases of microangiopathy undergoing pheresis at our institution for presumed TTP from May 2007 to April 2012. A total of 112 patients had PEX initiated for presumed TTP however 11 of these were later determined to have some other etiology causing the constellation of symptoms and PEX was discontinued. The remaining 101 patients were entered into a database and further analyzed. Demographically, we captured patients from 30 of the 100 North Carolina counties because 3 other institutions in our state perform plasma exchange for TTP. ADAMTS13 activity and inhibitor levels were measured in 69 out of 101 patients. In our registry there were 80 patients with Idiopathic TTP and 21 patients with secondary TTP. Patients with idiopathic TTP were further divided based on the ADAMTS13 activity. Results:FeaturesIdiopathic TTP (80)Secondary TTP(21)Idiopathic TTP ADAMTS13 <10% (31)Idiopathic TTP ADAMTS13 >10% (16)Idiopathic TTP ADAMTS13 Unkwn(33)Age (median)47 (17-80)43 (17-69)45 (23-78)50 (21-65)42 (21-79)Sex (%females)6657676863Race (%African American)7276676281Bld Grp (most frequent)A+, 0+A+,O+A+O+A+Symptoms (most frequeCNS, GICNSCNSCNSCNSHematocrit (median)36 (12-39)23 (15-37)24.52526Platelet (median)1600017000110004800017000LDH (median)12161109138711611255Creatinine (median)1.51.41.23.92.1PEX (median)21 (3-160)21 (5-128)23 (8-91)12 (7-100)27 (3-64)Rituximab (no of pts)1811720Relapse (%)212825030>=1 relapse (no of pts)94NANANADeath (%)54309ADAMTS 13<10%(%)3828NANANAInhibitor (present or Abs243NANANAADAMTS 13>10%(%)2014NANANAADAMTS 13 Unknwn3857NANANAIdiopathic TTP (%)NANA382038Secondary TTP(%)NANA281457 Discussion:Our analysis demonstrated that TTP was more common in females, African American population with a median age group in the mid forties with neurological symptoms being the predominant symptom of presentation. While hematocrit was higher in patients with idiopathic TTP these patients were noted to have increased incidence of ADAMTS13 levels less than 10% with inhibitors as compared to those with secondary TTP. Idiopathic TTP patients had more incidence of multiple relapses and required more Rituximab in addition to PEX. We compared our results with the results published from the Oklahoma registry. Similar to the Oklahoma registry results patients with ADAMTS13 levels less than 10% had more severe thrombocytopenia, renal dysfunction, required more sessions of PEX, had higher relapses and percentage of death compared to patients with idiopathic TTP with ADAMTS13 levels more than 10%. Patients with ADAMTS13 less than 10% required more Rituximab during first diagnosis of idiopathic TTP. In this group blood group A+ was seen more often whereas blood group O+ was prevalent in the group with ADAMTS more than 10%. Comparison amidst these groups brought out similarities between two distinct registries in the US. Our registry is another large registry of patients similar to the Oklahoma TTP registry. While many similarities are seen with the Oklahoma group there were a few differences as cited above. Disclosures:No relevant conflicts of interest to declare.

A case of thrombotic thrombocytopenic purpura induced by acute pancreatitis

Thrombotic thrombocytopenic purpura (TTP) is a multisystemic microvascular disorder that may be caused by an imbalance between unusually large von Willebrand factor multimers and the cleaving protease ADAMTS13. In acquired TTP, especially in secondary TTP with various underlying diseases, the diagnosis is difficult because there are many cases that do not exhibit severe deficiency of ADAMTS13 or raised levels of ADAMST13 inhibitors. It is well known that collagen disease, malignancy, and hematopoietic stem cell transplantation can be underlying conditions that induce TTP. However, TTP induced by acute pancreatitis, as experienced by our patient, has rarely been reported. Our patient completely recovered with treatments using steroids and plasma exchange (PE) only. In cases where patients develop acute pancreatitis with no apparent causes for hemolytic anemia and thrombocytopenia, the possibility of TTP should be considered. Treatments for TTP including PE should be evaluated as soon as a diagnosis is made.

Letter to the editor Cyclophosphamide-rescued plasmapheresis-unresponsive secondary thrombotic thrombocytopenic purpura caused by Sjögren’s syndrome

Letter to the editor Cyclophosphamide-rescued plasmapheresis-unresponsive secondary thrombotic thrombocytopenic purpura caused by Sjögren’s syndrome

Rituximab Has Similar Efficacy in Treatment of Acute Refractory or Chronic Relapsing Idiopathic Thrombotic Thrombocytopenic Purpura (TTP) and Refractory Secondary TTP: A Systematic Review

Abstract 4673 Background:Thrombotic thrombocytopenic purpura (TTP) is a potentially life-threatening disorder. Secondary TTP was known to be more resistant to plasma exchange and have higher mortality. Limited clinical data suggest that rituximab may be effective in the treatment of acute refractory or chronic relapsing nonfamilial idiopathic TTP (ITTP) as well as refractory secondary TTP (STTP). We performed a systematic review to evaluate the comparative efficacy of rituximab in ITTP and STTP. Method:An electronic literature search of Medline, CINAHL and the Cochrane library databases using the terms “rituximab” and “thrombotic” yielded 179 articles from March 2002 to June 2011. Studies were included if they met the following criteria: TTP in a first episode or subsequent relapse and TTP refractory to plasma exchange. Exclusion criteria were prophylactic administration of rituximab to patients in remission and familial TTP. Secondary TTP cases were author-defined. Case series without extractable individual data were excluded. Two-Tailed Fisher Exact Test was used to investigate the difference in complete remission rates between ITTP and STTP. Independent-Samples Mann-Whitney U Test was applied to detect the difference in platelet recovery days. Result:20 case series and 33 case reports including a small prospective study were eligible. Individual data of 139 patients from Europe, Asia, Australia, South and North America were analyzed. Overall, median age was 40 years (range: 1–72). Male constituted 30% and female 70%. Complete remission rate was 88% (90 out of 102) and 84% (31 out of 37) for ITTP and STTP respectively. There was no statistically significant difference in complete remission rates between the two groups (Two-Tailed Fisher Exact Test p value = 0.569). Median follow-up time was 12 months. Median platelet recovery (more than 150×109/L) from the first dose of rituximab was 8 days (range: 2–74) and 19 days (range: 7–90) for ITTP and STTP respectively. The distribution of platelet recovery days was the same between ITTP and STTP (Independent-Samples Mann-Whitney U Test p value = 0.132). Conclusion:Rituximab has the same efficacy in both STTP and ITTP in terms of response rate and platelet recovery days. It appears to be effective and well-tolerated. We recommend the use of rituximab as a salvage therapeutic modality in refractory acute or chronic relapsing nonfamilial idiopathic as well as secondary TTP. Disclosures:No relevant conflicts of interest to declare.

Thrombotic Thrombocytopenic Purpura After Prophylactic Cefuroxime Axetil Administered in Relation to a Liposuction Procedure

Thrombotic thrombocytopenic purpura (TTP) or Moschcowitz's syndrome is characterized by platelet and von Willebrand factor (vWF) deposition in arterioles and capillaries throughout the body, which results in organ ischemia. The diagnostic pentad characterizing TTP consists of thrombocytopenia, microangiopathic hemolytic anemia (MAHA), fever, neurologic manifestations, and renal insufficiency. In terms of type, TTP can be either idiopathic or secondary. The causes of secondary TTP include pregnancy, infections, pancreatitis, collagen vascular disease, cancer, bone marrow transplantation, and drugs (including cephalosporins). Postoperative TTP has been reported after vascular surgery, renal and liver transplantations, and orthopedic, urologic, and abdominal surgical procedures. Therapeutic plasma exchange (TPE) therapy has reduced the mortality rates, but sometimes patients may have to receive immunosuppressive drugs including vincristine (VCR). This report describes a 42-year-old woman with TTP after prophylactic usage of cefuroxime axetil in relation to a liposuction procedure who was treated successfully with plasma exchange and VCR. The patient fully recovered after 17 TPEs and three doses of VCR. At this writing, her TTP still is in remission after 6months of follow-up evaluation. To the authors' knowledge, this is the first report in the literature describing a patient with TTP after cefuroxime axetil administered in relation to a surgical procedure who was treated successfully with TPE and VCR.

Thrombotic Thrombocytopenic Purpura Associated with Mixed Connective Tissue Disease: A Case Report

Thrombotic thrombocytopenic purpura (TTP) is a multisystemic disorder characterized by microangiopathic hemolytic anemia and thrombocytopenia, which may be accompanied by fever, renal, or neurologic abnormalities. Cases are divided into acute idiopathic TTP and secondary TTP. Autoimmune diseases, especially systemic lupus erythematosus, in association with TTP have been described so far in many patients. In contrast, TTP occurring in a patient with mixed connected tissue disease (MCTD) is extremely rare and has only been described in nine patients. We describe the case of a 42-year-old female with MCTD who developed thrombocytopenia, microangiopathic hemolytic anemia, fever, and neurological symptoms. The patient had a good clinical evolution with infusion of high volume of fresh frozen plasma, steroid therapy, and support in an intensive care unit. Although the occurrence of TTP is rare in MCTD patients, it is important to recognize TTP as a cause of thrombocytopenia and hemolytic anemia in any patient with autoimmune diseases. Prompt institution of treatment remains the cornerstone of treatment of TTP even if plasma exchange is not available like what frequently happens in developing countries.

Thrombotic thrombocytopenic purpura: A single – Centre experience

We aimed to describe the characteristics, treatment regime, and 6-month all-cause mortality of thrombotic thrombocytopenic purpura (TTP) patients treated with total plasma exchange in the our clinic. Thirteen patients were included in the study. Mortality rates of TTP have improved over the last three decades but they are still too high according to modern therapy expectations. Etiology directed treatment should be added to total plasma exchange in secondary TTP cases. Based on TTPs’ immunologic etiology, immune modulator and immune suppressor agents have been applied together with total plasma exchange, but mostly in anecdotal case reports or with questionable responses.

Rituximab for managing relapsing or refractory patients with idiopathic thrombotic thrombocytopenic purpura--haemolytic uraemic syndrome.

Thrombotic thrombocytopenic purpura (TTP) is a rare disorder characterized by thrombocytopenia, microangiopathic haemolytic anaemia, neurological and renal abnormalities and fever1, with a mortality rate, in the absence of treatment, of almost 90%. Since such criteria do not distinguish TTP from haemolytic uraemic syndrome (HUS), the comprehensive term TTP-HUS is more approriate2. The standard therapy is urgent plasma exchange (PE)1, which reduces mortality to 10% or less3–9. Because of its dramatic effect on short and long-term outcome, it is now accepted that PE can be begun, in the absence of an alternative diagnosis, even when not all of the above criteria are fulfilled3,4,6,9,10. The evident advantage of early initiation of therapy along with the decreased diagnostic threshold has resulted in a 7-fold increase of patients treated with PE for TTP-HUS from 1981 to 199711. The symptoms of TTP are related to the presence of von Willebrand factor (VWF)-rich platelet thrombi in arterioles and capillaries. VWF is a multimeric plasma glycoprotein crucial for both platelet adhesion and aggregation, especially at the high shear rates present in the microvasculature. The size of VWF multimers is physiologically regulated in vivo by a specific metalloprotease, ADAMTS-13 (a disintegrin-like and metalloprotease with thrombospondin type 1 repeats)12. A severe deficiency of ADAMTS-13 (< 5% of normal activity) may be specific for TTP13 and it has been proposed that severe ADAMTS-13 deficiency now defines TTP14,15. Because ADAMTS-13 deficiency, whether idiopathic or caused by an autoantibody, provides a possible explanation for the effectiveness of PE (removal of the autoantibody by apheresis; supply of ADAMTS-13 by plasma replacement), it has been suggested that the levels of this metalloprotease can be used to guide treatment decisions14,16–19. At present it is not possible to establish the sensitivity of ADAMTS-13 deficiency for identifying patients who may respond to PE. In seven reports, 45% to 100% of patients with TTP were reported to have severe deficiency of ADAMTS-13 activity19–25 while such a high rate has not been described in those with HUS19,20,23. However, the interpretation of these studies is limited by the absence of explicit criteria for distinguishing patients with TTP from patients with HUS. PE has been proven effective even in patients without deficiency of ADAMTS-13 activity, which makes it difficult to understand how PE is benificial2. In conclusion, the role of ADAMTS-13 activity in the diagnosis and treatment decisions in patients with TTP or HUS remains unknown. Therapy with PE should be implemented in all patients with TTP-HUS and continued until the resolution of signs and/or symptoms and normalisation of laboratory tests; this can require long-term therapy. PE has some other disadvantages: first of all, it is not a risk-free procedure since a substantial number of major complications have been reported26,27. Furthermore, about 10% to 20% of TTP-HUS patients do not respond or have only an incomplete response2. Various different types of immunosuppressive treatment have been proposed for refractory patients14,29,30,32, including steroids and immunosuppressive or immune-modulating agents; however, the lack of robust data does not allow proper suggestion of such agents in the setting of acute refractory or chronic relapsing TTP28,32. Splenectomy has been proposed for patients with refractory or relapsing TTP, with reported remission rates of 50–100%29, but relapses have occurred in a considerable proportion of patients, most of them with severe ADAMTS-13 deficiency2,29,33,35. It has recently been shown that splenectomy can cause the disappearance of antibodies, normalisation of ADAMTS-13 activity and clinical remission in cases of refractory/relapsing TTP associated with anti-ADAMTS-13 autoantibodies. Other authors reported a low frequency of relapses in a large cohort of patients who underwent splenectomy30. Rituximab, a chimaeric monoclonal antibody directed against the CD20 antigen present on B lymphocytes, is used in lymphoma patients and those with rheumatoid arthritis33. Its action relies on clearance of the B lymphocytes responsible for antibody production by complement-dependent cytotoxicity, antibody-dependent cellular cytotoxicity or directly by inducing apoptosis31,33. The understanding that ADAMTS-13 deficiency could be antibody-mediated first provided the rationale for the use of rituximab in TTP-HUS12, but its reported effectiveness even in TTP-HUS patients without antibody-mediated ADAMTS-13 deficiency as well as in cases of refractory/relapsing cases makes this monoclonal antibody a very attractive therapeutic agent33–35. The data suggest that the drug may not simply decrease ADAMTS-13 autoantibody production by depleting B cells, but that it may have additional mechanisms of action. Kameda et al.34 suggested that B-cell depletion by rituximab reduces excessive cytokine production in patients with secondary TTP, thus containing the level of VWF multimers within the normal range. At present, only data from case series have been published and many questions remain open regarding the target population, timing of initiation, duration of treatment and concomitant PE34–49. Here we describe four patients with refractory/relapsing idiopathic TTP-HUS who were successfully treated with rituximab (Table I). Table I Patients’ characteristics

TTP disease course is independent of myeloma treatment and response

TTP disease course is independent of myeloma treatment and response