Idiopathic Thrombotic Thrombocytopenic Purpura Patients Research Articles

A 14-Year Experience in the Management of Patients with Acquired Immune Thrombotic Thrombocytopenic Purpura in Northern Israel

Acquired idiopathic thrombotic thrombocytopenic purpura (I-TTP) is a life-threatening microangiopathic disorder usually treated with therapeutic plasma exchange (TPE). The current study assessed the role of rituximab in the treatment of complicated I-TTP. The sequence of TTP events was compared in a group of I-TTP patients treated with TPE and a cohort of refractory or relapsed patients who also received rituximab. This retrospective evaluation included 45 I-TTP patients, treated between January 2000 and October 2013, who underwent at least 3 TPE procedures and were followed up until December 2013 or death. Thirty-one patients with an uncomplicated course received TPE only. Fourteen patients had a complicated course due to either a primary refractory/exacerbated disease (n = 5) or relapse (n = 9) and received rituximab together with TPE. The median number of TPE procedures performed in the first TTP episode in the uncomplicated cohort and groups with primary refractory or relapsed TTP was 11, 27 and 45, respectively. The relapse rates per follow-up year in the uncomplicated I-TTP, primary refractory and relapsed I-TTP groups were 0.18, 0.2 and 0.6 episodes, respectively. After rituximab therapy this rate dropped to 0.2 per year in the relapsed subgroup. In conclusion, about a quarter of patients with I-TTP had a complicated course and experienced a major benefit from rituximab in terms of effectiveness and safety.

Clinical study on Rituximab in the treatment of idiopathic thrombotic thrombocytopenic purpura

目的观察利妥昔单抗（RTX）在特发性血栓性血小板减少性紫癜(ITTP)治疗中的价值。方法17例ITTP患者中9例采用RTX＋血浆置换＋糖皮质激素治疗（RTX组），8例采用血浆置换+糖皮质激素±免疫抑制剂（对照组）。RTX用法为375 mg/m2每周1次连续4次。监测患者血常规、LDH、ADAMTS13活性及抑制物、外周血B淋巴细胞百分比。观察两组患者的血浆置换次数/总量、缓解时间、复发率及不良反应发生情况。结果RTX组、对照组血浆置换次数中位数分别为5(2~8)、6(4~9）次，血浆置换总量中位数分别为9.6(4.0~15.4)、11.2(7.5~14.6)L。RTX组、对照组达到血液学缓解中位时间分别为15(5~20)d、22(7~36)d，达到免疫学缓解中位时间分别为2(2~8)、2(2~4）周。两组患者ADAMTS13活性均在2周后显著回升。RTX组随访期内无复发，对照组4例患者复发。RTX给药前及治疗后1周患者外周血B淋巴细胞百分比差异有统计学意义[(18.39±7.15)％对(2.19±5.11)%，P<0.001], 9个月后逐渐回升，治疗中未观察到RTX相关严重不良反应，但该组1例患者持续免疫学缓解7个月后死于肺部感染。结论RTX联合血浆置换和糖皮质激素治疗ITTP，能快速获得血液学甚至免疫学缓解，降低复发率，不良反应少，但需注意防治感染。

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.

Analysis of clinical and laboratory characteristics in 42 patients with thrombotic thrombocytopenic purpura from a single center in China

Thrombotic thrombocytopenic purpura (TTP) is a life-threatening disease characterized by microvascular platelet deposition and thrombus formation with resulting microangiopathic hemolytic anemia. Deficiency of the von Willebrand factor cleavage protease, also known as ADAMTS 13, has been implicated as an important etiological factor in TTP. Little studies were obtained on Chinese patients with TTP until now. Our aim was to analyze the clinical features, outcome and laboratory characteristics of Chinese TTP patients, and determine whether plasma ADAMTS 13 activity is decreased in TTP and its diagnostic value for TTP. Forty-two TTP patients (29 females; 13 males) admitted to our hospital from 1998 to 2010 were analyzed. There were 34 patients (81%) with the triad of TTP, including hemolytic anemia, thrombocytopenia and neurologic abnormalities; 7 (16.7%) had the classical pentad of TTP. Major etiologic factors were acquired autoimmunological abnormalities (31%); no familial TTP was identified in this series. The schistocytes of peripheral blood smears were present in all cases with a mean frequency of 4.6% (range from 0.3% to 13.4%). Plasma ADAMTS 13 activity was determined in 22 patients with the FRET-vWF86 assay. Only 4 idiopathic TTP patients (18.2%) had severe ADAMTS 13 deficiency (activity<10%); 9 (40.9%) had moderate decrease of ADAMTS 13 activity (activity: 10-40%); another 9 (40.91%) had normal ADAMTS 13 activity (>40%). T lymphocyte subpopulation was measured in 23 TTP patients with FACS Calibur; 14 of the 23 (60.9%) had significantly decreased CD4 cells count and CD4/CD8 ratio, suggesting cellular immune dysfunction may be involved in the pathogenesis of TTP. In the studies, plasmapheresis is the main therapeutic method. 26 of 31 patients (83.9%) accepting plasmapheresis achieved complete remission; those patients who only underwent plasma infusion had low remission rate (18.2%) and high mortality (9/11; 81.8%). Four patients with packed RBC infusion manifested transient exacerbation of neurologic or psychiatric symptoms. In conclusion, the diagnosis of TTP in China is still based on clinical features including evidence of microangiopathic hemolysis. Severe ADAMTS 13 activity deficiency might be a valuable indicator for idiopathic TTP diagnosis. Further studies are needed to determine the real value of ADAMTS 13 activity for TTP diagnosis and whether T lymphocytes subset dysregulation plays important role in TTP pathogenesis.

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.

Antibody Against Macrophage Receptor with Collagenous Structure (Anti-MARCO IgG) in Thrombotic Thrombocytopenic Purpura Patients.

Abstract 2201Idiopathic thrombotic thrombocytopenic purpura (TTP) is typically associated with severe ADAMTS13 deficiency due to the production of autoantibodies against ADAMTS13. Recent studies have demonstrated that B cell activating factor (BAFF), a TNF family member known to promote activation and survival of autoreactive B cells, is increased in TTP patients (Thomas et al. 2011 155:620 Br J Haematol; Watanaboonyongcharoen et al. 2011, AABB Abstract # 1118421). We hypothesized that high BAFF levels in TTP results in loss of B cell tolerance and the production of autoantibodies. Since defective clearance of apoptotic cells by macrophages has been found in autoimmune diseases, antibodies against MARCO (Macrophage Receptor with Collagenous structure) represented good candidate for study as a potentially pathophysiologically relevant autoantibody. Such anti-MARCO antibodies may lead to defective apoptotic cell clearance and the development of TTP. We measured anti-MARCO antibodies by ELISA and Western blot in 34 idiopathic TTP patients between 1999 and 2012: 25 female and 9 male with a median age of 40 years (range 25–72). All patients were diagnosed on the clinical basis of microangiopathic hemolytic anemia and thrombocytopenia without any other cause. ADAMTS13 activity and the presence of anti-ADAMTS13 inhibitor tests were performed in all patients. Fifty percent of patients had ADAMTS13 activity less than 10%, while 56% had ADAMTS13 inhibitor. All 34 patients underwent therapeutic plasma exchange (TPE) daily until the platelet count was at least 150 × 109/l for two consecutive days. High dose steroids were initiated immediately after first TPE. While direct binding ELISA did not yield specific results due to high background, specific MARCO bands were detected by Western blotting of recombinant MARCO protein with patient plasma IgG. Ninety-seven percent of patients with TTP (33/34) were positive for anti-MARCO IgG antibody compared to forty percent (10/25) of healthy controls, p < 0.001 (Table 1). As a surrogate for antibody titer, intensity of each Western blot band was quantified by densitometry using NIH ImageJ software. Patients with TTP had significantly increased anti-MARCO IgG as defined by the densitometric area under the curve (1.3 × 103; range 0–8.2 × 103) compared to healthy controls (0, range 0–4.5 × 103), p < 0.001. A cut-off point for high titer anti-MARCO IgG was calculated by using mean + 2SD of the area under the curve (AUC) of anti-MARCO IgG Western blot band density measured in healthy controls. Patients with an increased amount of anti-MARCO IgG (AUC > 2.9× 103) tended to have a higher relapse rate compared to those with normal anti-MARCO IgG (4 of 6 patients [67%] vs. 10 of 28 patients [36%], respectively, p = 0.20), although statistical significance was not reached due to the limited number of patients. Thus, for the first time, we identify anti-MARCO IgG in idiopathic TTP, suggesting a role for macrophage inhibition in the pathophysiology of TTP. Studies of anti-MARCO antibodies in larger numbers of patients may lead to development of a novel prognostic marker for TTP patients.Table 1Presence of anti-MARCO IgG on Western blotAnti-MARCO IgGPopulation groupTTP n (%)Healthy n (%)Yes, (n = 43)33 (97)10 (40)No, (n = 16)1 (3)15 (60)p < 0.001. Disclosures:No relevant conflicts of interest to declare.

Efficacy of 5% Albumin and Fresh Frozen Plasma (AFFP) Versus Fresh Frozen Plasma (FFP) only as Replacement fluid in Plasma Exchange for Thrombotic Thrombocytopenic Purpura (TTP)

AbstractAbstract 272The treatment of Thrombotic Thrombocytopenic Purpura (TTP) with therapeutic plasma exchange (TPE) with Fresh Frozen Plasma (FFP) and/or Cryopoor Plasma (CPP) replacement is well established. This process adds plasma ADAMTS-13 activity and removes plasma ADAMTS-13 inhibitor. Limited data has indicated combination of 5% albumin in the first half of the procedure followed by FFP in the second half of the procedure is effective in treating TTP. Theoretical calculation of addition of exogenous ADAMTS-13 is still substantial because ADAMTS-13 infused initially is removed as the plasma exchange procedure progresses. A 50% reduction of FFP would decrease the number of donor exposures and transfusion reactions associated with human plasma. Further, plasma of limited supply, such as AB plasma, can be more effectively used.We report a retrospective comparison of TPE for TTP using all FFP versus 5% Albumin/FFP (AFFP) replacement fluid. One health system with two closely connected tertiary campuses with common Hematology/Oncology services and Transfusion Medicine services treated 17 idiopathic TTP patients (March/2009 – June/2012) with documented very low ADAMTS-13 levels (<10) and high inhibitor levels (≥0.4). All other thrombotic microangiopathies were excluded from this comparison. One campus treated 10 patients with FFP and the other campus treated 7 patients with AFFP. Daily one plasma volume TPE was performed until target platelet count was achieved and the patient was then tapered off TPE. For AFFP replacement, 50% of the replacement fluid was 5% albumin given in the first half of the procedure followed by FFP for the second half. Additional medical therapy was managed by the same Hematology/Oncology service.Table 1 shows that the FFP versus the AFFP groups at presentations are comparable. Table 2 indicated FFP versus AFFP treatment is comparable. For the FFP and AFFP groups respectively, mean number of total procedures: 16 vs. 14, length of time from first TPE to last TPE 19 vs. 22 days, Relapses 2 vs. 2, and deaths 1 vs. 0. Conclusion:The use of AFFP as replacement fluid for idiopathic TTP does not appear to be inferior to 100% FFP replacement. Length of treatment, rate of recovery, and relapse rate are comparable. There were more deaths in the FFP cohort but the low number of observations limits the significance. AFFP fluid replacement should be considered for TPE in idiopathic TTP. [Display omitted] Disclosures:No relevant conflicts of interest to declare.

Finishing the Picture: Clopidogrel Is Indeed the Most Common Drug Associated with Thrombotic Thrombocytopenic Purpura (TTP) In FDA Databases: Its Mechanism, Laboratory Findings, Clinical Features, and Epidemiology Differ From That Associated with Ticlopidine

AbstractAbstract 1527In 1998, 60 persons developed TTP between two and 12 weeks after initiation of ticlopidine therapy. We predicted that a newer thienopyridine, clopidogrel, upon FDA approval in 1999, would be associated with TTP. Cleveland Clinic physicians predicted that because of different metabolites, TTP following clopidogrel would not occur. We initiated an intensive 11-year multifaceted prospective pharmacovigilance program to characterize all clopidogrel-associated TTP instances and to evaluate epidemiologic, clinical and laboratory findings. In 1999, 11 cases of TTP occurred within 0 to 14 days following clopidogrel-initiation from queries of medical directors of plasma exchange centers in Houston, Chicago, Boston, Indiana, North Carolina, Baltimore, and Cincinnati- none of which were reported to the FDA. Since then, FDA's MedWatch database identified clopidogrel as the most common drug associated with reported TTP cases (n=197). (Table 1) Case reporting to the FDA decreased by 90% following toxicity description in Direct-To-Consumer advertisements beginning in 2006. Epidemiologic estimates suggest that 1 TTP occurs among 15,000 to 80,000 clopidogrel-treated persons (estimation efforts), versus rates of 1 TTP per 1,600 to 5,000 ticlopidine users (based on data obtained from interventional cardiology laboratories and plasmapheresis centers). Antibodies to ADAMTS-13 were evaluated for two of the first 11 patients with clopidogrel-associated TTP- both had antibodies to ADAMTS13- and developed spontaneous TTP relapses. After evaluating an additional 24 clopidogrel-associated TTP cases, these cases were recharacterized as idiopathic TTP patients (they were the only clopidogrel-associated TTP individuals exposed to a thienopyridine who had spontaneous relapses and the only clopidogrel-associated TTP patients to have detectable antibodies to ADAMTS13 and severe ADAMTS13 deficiency). Epidemiologic studies funded by clopidogrel's manufacturer reported that TTP occurrence rates did not increase following 1999 FDA approval of clopidogrel and there was no statistical association of clopidogrel with TTP. Pharmacovigilance studies of plasmaphersis centers and national referral laboratories in Japan and Canada identified 20 individuals who developed TTP within two weeks of clopidogrel initiation. Several clinicians reported again that the association of clopidogrel with TTP likely represented an epi-phenomenon. Five published case reports described TTP developing shortly after clopidogrel initiation- none had ADAMTS13 antibodies or deficient ADAMTS13 activity levels. Laboratory studies reported that antibodies to ADAMTS-13 were identified in 100% of 30 ticlopidine-associated TTP patients and 0% of eight clopidogrel-associated TTP patients and severe ADAMTS13-deficiency occurred in 80% of ticlopidine patients and 0% of clopidogrel patients (p<0.05 for each). These laboratory findings for clopidogrel-associated TTP supported the hypothesis that the association of clopidogrel with TTP represented a causal relationship. Clinical studies indicated that ticlopidine- versus clopidogrel-associated TTP differed with respect to platelet counts < 20,000/mm3 (84% versus 60%; p< 0.05) and onset within two to 12 weeks of drug initiation (90% versus 26%, p<0.05). We conclude that: instances of TTP following clopidogrel therapy occurred; clinical and laboratory characteristics of TTP following clopidogrel initiation differed from those reported with ticlopidine; and clopidogrel is the most common drug currently associated with TTP in the MedWatch database. Without this pharmacovigilance effort, the association of clopidogrel with TTP would have gone unnoticed. With this effort, we identified clopidogrel as the most common drug associated with TTP, as a proximate cause of TTP in rare instances, and reported that clinical and laboratory findings, prognosis, and therapeutic approaches differed between clopidogrel- and ticlopidine-associated TTP.Table 1:Epidemiology of Ticlopidine and Clopidogrel associated TTPTotal cases 1999-2009Cases since 2002EpidemiologyClopidogrel induced TTP MA1971401 per 1,600 to 1 per 5000 casesTiclopidine induced TTP87101 per 15,000 to 1 per 80,000 casesFigure 1 FDA reports of Thienopyridine-associated TTP by yearFigure 2 Following Ticlopidine and Clopidogrel over time Disclosures:Bennett:Pfizer: Consultancy.

Evaluation and Clinical Application of a New Method for Detecting ADAMTS13 Activity.

Abstract 2134Poster Board II-111 Introduction:A severe deficiency of ADAMTS13 activity contributes to the pathogenesis of thrombotic thrombocytopenic purpura (TTP). Measuring the activity of ADAMTS13 is helpful for the diagnosis of TTP and the prognostic monitor in TTP patients. Most available assays are cumbersome and costly, and not appropriate for routine laboratories. ADAMTS13 cleaves the von Willebrand factor (VWF) within the domain A2, which locates between the domains A1 and A3. Therefore, specific assays for ADAMTS13 activity could be based on the different structure of VWF before and after the cleavage. Materials and Methods:To determine the activity of ADAMTS13, a new simple method has been developed in this study. Firstly, plasma samples were exposed in denaturing condition to allow cleavage of VWF by ADAMTS13. Then, the ADAMTS13 activity was measured with two novel monoclonal antibodies (SZ-129 and SZ-125), which are specifically recognize the VWF A1 and A3 domain, respectively, by using a two-site sandwich ELISA. Comparing with a residual-collagen binding assay (R-CBA), plasma ADAMTS13 activities in 161 samples were assessed, and the inhibitory activities of ADAMTS13 autoantibodies in 24 TTP patients were determined. The relationship of these two assays was analyzed by linear correlation, and the sensitivity and specificity of the new assay was also evaluated. ResultsOur results showed that plasma ADAMTS13 activities determined by the new assay were consistent with those of R-CBA, the squared correlation factor was 0.9183 of the two assays, and the coefficient of variation for the new assay was 6.17%. In 23 idiopathic TTP patients, the inhibitor activities of ADAMTS13 autoantibodies were ranged from 12% to 100%, while no inhibitory activity was detected in one hereditary TTP patient. ConclusionsThis new and simple assay for ADAMTS13 activity could be used routinely in clinic to determine the activity of ADAMTS13. Disclosures:No relevant conflicts of interest to declare.

Two cases of refractory thrombotic thrombocytopenic purpura associated with collagen vascular disease were significantly improved by rituximab treatment

Thrombotic thrombocytopenic purpura (TTP) is a rare disorder of small vessels. TTP is associated with deficiency of the von Willebrand factor-cleaving protease, ADAMTS13, and its inhibitor. Low ADAMTS13 activity is present in most of idiopathic TTP patients. The prognosis of TTP was improved by plasma exchange treatment, which replaces the ADAMTS13 and removes ADAMTS13 inhibitor. However, ADAMTS13 activity is normal in some TTP patients. These are found among the secondary TTP patients associated with collagen disease, hematopoietic stem cell transplantation, malignancy, or drugs. In addition, most of them do not respond to plasma exchange. On the other hand, several reports demonstrated that rituximab, which is an anti-CD20 monoclonal antibody, is effective for refractory TTP cases caused by ADAMTS13 deficiency. It is considered that the effect of rituximab is associated with disappearance of ADAMTS13 inhibitor. However, rituximab therapy was effective for the TTP patients with normal ADAMTS13 activity in our cases. We considered another mechanism of rituximab for TTP cases.

Disseminated Malignancy Misdiagnosed as Thrombotic Thrombocytopenic Purpura: A Report of 10 Patients and a Systematic Review of Published Cases.

Patients with disseminated malignancy who present with microangiopathic hemolytic anemia and thrombocytopenia may be misdiagnosed as thrombotic thrombocytopenic purpura (TTP), resulting in inappropriate plasma exchange treatment, a procedure with major risk, and delay of appropriate chemotherapy. We report the 17 year experience of The Oklahoma TTP-HUS Registry, 1989–2005, and a systematic review of previously published case reports. Ten of 335 consecutive patients in the Oklahoma Registry who were initially diagnosed with their first episode TTP and treated with plasma exchange were subsequently discovered to have disseminated malignancy; only one had a history of cancer. These 10 patients were compared to the 133 concurrent patients with idiopathic TTP.Disseminated malignancy (n=10)Idiopathic TTP (n=133)PAge (years)56470.106Sex (% female)30%73%0.008Duration of sx (days)2180.005Presenting sxWeakness70%53%0.347cough, dyspnea70%26%0.007Fever50%31%0.292abdominal pain40%35%0.745Nausea/vomiting20%53%0.052Neurologic abnormalitiesSevere20%47%0.128Minor60%29%None20%24%Laboratory datahematocrit (%)21220.868platelet count (103/ml)21,00013,0000.328creatinine (mg/dL)2.42.00.761LDH (U/L)289412600.045ADAMTS13Median activity (%)50(8)23 (81)0.167<5% activity (% of pts)030%0.102Response to PE10%82% (125)<0.001Death (within 30 days)90%20%<0.001Data are median values. P-value for neurologic symptoms compares distribution of abnormalities. Number of patients who had ADAMTS13 measured is in parentheses. 8 idiopathic TTP patients never had plasma exchange (PE).Patients with disseminated malignancy had a longer duration of symptoms, were more often men, had more frequent presence of respiratory symptoms, higher LDH levels, more often failed to respond to plasma exchange treatment, and had a higher mortality. Neurologic abnormalities, hematocrit, platelet count, and serum creatinine were not different between the two groups. Diagnosis of malignancy was made by bone marrow biopsy in 6 patients but not until autopsy in 2 patients. A systematic review identified 19 additional patients, reported from 1965 to 2005, in whom TTP or HUS was initially suspected and systemic malignancy subsequently discovered. Only 5 patients had a history of cancer. Malignancy was not diagnosed until autopsy in 6 patients. Fourteen different malignant disorders were diagnosed in these 29 patients.CONCLUSIONS: Disseminated malignancy may be occult and may mimic TTP. A search for systemic malignancy, including a bone marrow biopsy, is appropriate when patients diagnosed with TTP have atypical clinical features or fail to respond to plasma exchange.

Inhibitory autoantibodies against ADAMTS-13 in patients with thrombotic thrombocytopenic purpura bind ADAMTS-13 protease and may accelerate its clearance in vivo.

Many patients with acquired thrombotic thrombocytopenic purpura (TTP) harbor autoantibodies that may bind and/or inhibit ADAMTS-13 proteolytic activity and accelerate its clearance in vivo. To test this hypothesis, we determined ADAMTS-13 activity and antigen levels in parallel plasma samples from patients clinically diagnosed with TTP. Collagen binding, GST-VWF73 and FRETS-VWF73 assays were used to determine ADAMTS-13 activity and to detect inhibitory autoantibodies. Enzyme-linked immunosorbent assay (ELISA) and immunoprecipitation plus Western blotting (IP/WB) were used to detect total anti-ADAMTS-13 IgG (inhibitory and non-inhibitory). Among 40 patients with TTP (21 idiopathic and 19 non-idiopathic), inhibitory autoantibodies were detected (by FRETS-VWF73) in 52% of idiopathic and 0% of non-idiopathic TTP patients. In contrast, non-inhibitory IgG autoantibodies were detected in 29% of idiopathic and 50% of non-idiopathic TTP patients. The concentration of inhibitory IgG autoantibody in idiopathic TTP patients was significantly higher than that of non-inhibitory IgG in either idiopathic or non-idiopathic TTP patients. Idiopathic TTP patients demonstrated significantly reduced ADAMTS-13 activity compared with non-idiopathic patients, but only slightly lower ADAMTS-13 antigen levels. Interestingly, patients with inhibitory autoantibodies exhibited significantly lower ADAMTS-13 antigen levels than those with only non-inhibitory IgG autoantibodies or no autoantibody. Serial plasma exchanges increased levels of ADAMTS-13 activity and antigen concurrently in patients with inhibitory autoantibodies. The identification of severe ADAMTS-13 deficiency and autoantibodies or inhibitors appears to be assay-dependent; the inhibitory IgG autoantibodies, in addition to binding and inhibiting ADAMTS-13 proteolytic activity, may accelerate ADAMTS-13 clearance in vivo.

Pathogenesis of Thrombotic Thrombocytopenic Purpura: ADAMTS13 Deficiency and Beyond

Thrombotic thrombocytopenic purpura (TTP) is characterized by the systemic deposition of platelet thrombi with abundance of von Willebrand factor (vWF) in the arterioles and capillaries. Recently, vWF protease (ADAMTS13) activity was found to be severely deficient in hereditary TTP as well as acquired idiopathic TTP. Homozygous or compound heterozygous mutations of ADAMTS13 gene were demonstrated in hereditary TTP. Autoantibodies against ADAMTS13 were present in majority of patients with idiopathic TTP and ticlopidine- and clopidogrel-associated TTP. The deficiency of ADAMTS13 leaves unchecked the hyperadhesive vWF unfolded under high shear stress in the microvessels, resulting in the formation of platelet thrombi, which in turn causes TTP. ADAMTS13 activity is usually normal in hemolytic uremic syndrome. Approximately 0 to 67% of idiopathic TTP patients reported may not be severely deficient of ADAMTS13. Therefore, acquired TTP is not caused by ADAMTS13 deficiency alone and may be triggered by certain stimuli that possibly cause autoimmune reactivity to ADAMTS13, and also induce platelet aggregation either dependent on or independent of vWF, and/or vascular injury, to account for variable clinical and laboratory presentations. Plasma samples from TTP patients have been shown to induce endothelial cell apoptosis and activation. Platelet aggregating factors independent of vWF purified from the plasma of a subset of TTP patients have been reported and shown to be inhibited by normal plasma and immunoglobulin G purified from normal plasma. Defective fibrinolysis and abnormal natural coagulation inhibitors may enhance the thrombi formation in the microcirculation.

Defective processing of unusually large von Willebrand factor multimers and thrombotic thrombocytopenic purpura

Defective processing of unusually large von Willebrand factor multimers and thrombotic thrombocytopenic purpura