ADAMTS13 Deficient Research Articles

DEFICIENCY OF ADAMTS-13 IN SEPSIS PATIENTS AND ITS CORRELATION WITH MORBIDITY/ MORTALITY

Objective: To detect ADAMTS-13 deficiency in sepsis patients and its effect on in-hospital morbidity and mortality in adult patients of sepsis.
 Study Design: Cross sectional study.
 Place and Duration of Study: Armed Forces Institute of Pathology (AFIP) and Combined Military Hospital (CMH) Rawalpindi, from Apr 2017 to Apr 2018.
 Methodology: All indoor patients admitted at Combined Military Hospital Rawalpindi and diagnosed as suffering from sepsis at Armed Forces Institute of Pathology according to the guidelines of the Critical Care Society of Medicine Consensus Conference Committee. Forty sepsis patients were recruited for the study. Two groups were formed on the basis of ADAMTS-13 antigen levels, non-deficient and deficient. Basic haematological and clinical parameters were recorded. Levels of ADAMTS-13 antigen were analyzed by using Technozyme kit byenzyme-linked immunosorbent assay (ELISA) and level less than 0.40 IU/ml was taken deficient as defined by manufacturer. Comparison was done between ADAMTS-13 deficient and non-deficient group with regard to clinical and haematological characteristics, ICU stay, hospital admission days and in-hospital mortality. Healthy controls of same age and gender were also observed for ADAMTS-13 antigen level.
 Results: Among total 40 sepsis patients, thirty two (80%) were males and eight (20%) were females with a mean age of 61 ± 15 years (range: 30-85 years). ADAMTS-13 deficiency (<0.40 IU/ml) was found in 28 (70%) of patients while 12 (30%) had normal antigen levels. In patients with ADAMTS-13 deficiency, twenty four (85.7%) had low platelet levels <150 x 109/l, mean hospital stay 19.2 ± 7.6 days and in-hospital mortality was seen in eight (28.6%) patients, in comparison of non-deficient group in which platelet levels were equal or >150 x 109/l, mean hospital stay was 10.2 ± 3.6 days and in-hospital mortality was in one (8.3%) patient respectively. ADAMTS-13 antigen level was found sufficient in healthy controls.
 Conclusion: Majority of the sepsis patients were found ADAMTS-13 deficient. Deficiency exhibit long term hospital admission, thrombocytopenia and increase in hospital mortality. ADAMTS-13 deficiency might play a role in sepsis induced thrombocytopenia and in hospital mortality. More studies are recommended on the subject with larger sample size to evaluate its role in sepsis.

Immature platelet dynamics correlate with ADAMTS13 deficiency and predict therapy response in immune-mediated thrombotic thrombocytopenic purpura

IntroductionThrombotic thrombocytopenic purpura (TTP) requires prompt initiation of therapeutic plasma exchange (TPE) to avoid significant morbidity and mortality. ADAMTS13 activity testing defines TTP, however, at most institutions this is a send-out test and therapy is often initiated prior to measurement availability. We describe our experience looking at absolute immature platelet counts (A-IPC) in patients suspected with TTP at presentation and in response to therapy. Materials and methodsForty-eight patients treated for suspected TTP with A-IPC measure on admission and during hospitalization met inclusion criteria. Of these patients, sixteen had new-onset TTP (ADAMTS13 < 10%), ten were relapsing patients (first diagnosis prior to study period), and 22 were classified as non-TTP (ADAMTS13 ≥ 10%). ResultsPatients with ADAMTS13 deficiency (TTP) had A-IPC different from those without deficiency. A-IPC of 1–2 × 109/L at presentation had high sensitivity and specificity with a negative predictive value of 95.5 to 100%. Two-to-three-fold increases in A-IPC from count prior to TPE initiation was limited to ADAMTS13 deficient patients who was the group responding to therapy. Increases were higher in patients with new disease onset compared to relapsing patients (p = 0.018). Likewise, relapsing patients' A-IPC appeared dependent upon platelet count at time of relapse. A-IPC predicted and correlated with ADAMTS13 deficiency in new-onset TTP (p = 0.0002). ConclusionsOnly patients with A-IPC-fold increases responded to TPE with platelet count normalization. Our results represent a proof of concept that A-IPC measurements can supplement ADAMTS13 testing and determine response to TPE. Future studies are needed to establish ways to apply these findings in the setting of suspected TTP.

Non-O blood group thrombotic thrombocytopenic purpura patients take longer to recover as measured by number of therapeutic plasma exchanges needed for platelet recovery

IntroductionTherapeutic plasma exchange (TPE) is mainstay therapy for thrombotic thrombocytopenic purpura (TTP). However, it remains controversial if ABO type influences diagnosis or time to remission. Materials and methodsWe investigated if ABO type influences length of TPE regimen in TTP patients with ADAMTS13 deficiency at our institution. Seventy out of 71 patients with suspected TTP who had ADAMTS13 activity measured were included. ADAMTS13 activity <10% defined those with idiopathic/acquired TTP (41/70). ResultsWe found that among patients with ADAMTS13 deficiency, non-O patients required a significantly greater number of TPE (NoP) compared to O patients (p = 0.039). Additionally, patients with ADAMTS13 deficiency regardless of ABO type needed more TPE to achieve platelet recovery compared to those patients without deficiency (p = 0.00002). In regard to other variables that may affect response to therapy in TTP patients, we found no association between obesity and NoP; however, obesity rate was higher among ADAMTS13 deficient patients compared to overall obesity rate of our regional general population. Likewise, were found that blood group O did not occur with greater frequency in our cohort.Conclusions: Our data indicates that ABO may affect the NoP patients required for disease remission. We found that non-O patients needed more procedures to overcome their disease. Further work with greater number of patients will be needed to determine if specific non-O blood types require more procedures to recover their platelet count.

Role of ADAMTS13 in diet-induced liver steatosis.

Previous studies, predominantly based on increased or decreased plasma levels, have reported conflicting data on a potential functional role of ADAMTS13 in the pathogenesis of liver diseases, including non‑alcoholic steatohepatitis (NASH). The aim of the current study was to evaluate whether ADAMTS13 deficiency affects development of NASH. Therefore, male wild‑type (WT) and Adamts13 deficient (Adamts13‑/‑) mice were kept on a steatosis‑inducing diet devoid of methionine and choline (MCD) or a control diet (MCC) for 4weeks. Induction of NASH did not affect plasma ADAMTS13 antigen levels of WT mice. MCD as compared with MCC feeding resulted in reduced body and liver weight with no differences between the genotypes. Plasma levels of the liver enzymes AST and ALT were significantly higher for MCD vs. MCC fed Adamts13‑/‑ and WT mice, however were not different between the genotypes. Liver triglyceride levels were also higher after MCD feeding, but were not different between WT and Adamts13‑/‑ mice. Adamts13‑/‑ mice on the two diets exhibited higher insulin sensitivity when compared with WT mice. On the MCC diet, the genotype did not show clear histological abnormalities in the liver, whereas severe steatosis and fibrosis were observed on MCD diet, however were comparable for both genotypes. This was supported by comparably enhanced hepatic expression in the two genotypes on MCD diet of the steatosis marker CD36 and of the fibrosis marker tissue inhibitor of metalloproteinase 1. Thus, the results of the current study do not support a functional role of ADAMTS13 in this murine model of NASH.

ADAMTS13 deficiency promotes microthrombosis in a murine model of diet-induced liver steatosis.

ADAMTS13 cleaves ultralarge multimeric von Willebrand Factor (VWF), thereby preventing formation of platelet-rich microthrombi. ADAMTS13 is mainly produced by hepatic stellate cells, and numerous studies have suggested a functional role of ADAMTS13 in the pathogenesis of liver diseases. The aim of our study was to investigate a potential role of ADAMTS13 in formation of hepatic microthrombi and development of non-alcoholic steatohepatitis (NASH), and furthermore to evaluate whether plasmin can compensate for the absence of ADAMTS13 in removal of thrombi. Therefore, we used a model of high-fat diet-induced steatosis in Adamts13 deficient (Adamts13-/-) and wild-type (WT) control mice. Microthrombi were more abundant in the liver of obese Adamts13-/- as compared to obese WT or to lean Adamts13-/- mice. Obese Adamts13-/- mice displayed lower platelet counts and higher prevalence of ultra-large VWF multimers. Hepatic plasmin-α2-antiplasmin complex levels were comparable for obese WT and Adamts13-/- mice and were lower for lean Adamts13-/- than WT mice, not supporting marked activation of the fibrinolytic system. High fat diet feeding, as compared to normal chow, resulted in enhanced liver triglyceride levels for both genotypes (p < 0.0001) and steatosis (p < 0.0001 for WT mice, p = 0.002 for Adamts13-/- mice) without differences between the genotypes. Expression of markers of inflammation, oxidative stress, steatosis and fibrosis was affected by diet, but not by genotype. Thus, our data confirm that obesity promotes NASH, but do not support a detrimental role of ADAMTS13 in its development. However, Adamts13 deficiency in obese mice promotes hepatic microthrombosis, whereas a compensatory role of plasmin in removal of microthrombi in the absence of ADAMTS13 could not be demonstrated.

Neutrophil Recruitment Is Regulated By Adamts-13 in a Murine Model of Invasive Aspergillosis

▪Introduction: During inflammation von Willebrand factor (VWF) multimers are secreted as an acute phase protein whereupon the size and the prothrombotic activity play an essential role. The size of VWF multimers is regulated by the specific proteolytic activity of ADAMTS-13 (a disintegrin and metalloprotease with ThromboSpondin type 1 repeats-13) which is diminished under several pathological conditions. Employing a murine model of invasive pulmonary aspergillosis (IPA) we aimed to determine the relevance of this regulatory pathway for innate inflammatory responses and polymorphonuclear neutrophil (PMN) recruitment which is crucial for fungal clearance and survival.Methods: IPA was induced by intratracheal application of Aspergillus fumigatus (A. fumigatus) conidia in wildtype (129/Sv/Pas) or Adamts13 deficient (Adamts13-/-) mice. 24 h after infection some mice were sacrificed for analysis of fungal load and histology. To assess fungal load as CFU lung homogenates were plated and cultured on Sabourough agar plates. Paraffin sections of the lungs were prepared and stained with mouse complement component C3d antibody for histological analysis. In addition, degranulation, oxidative burst activity and CD62L shedding were assessed in PMN of wildtype and Adamts13-/- mice. Chemotactic properties of A. fumigatus -activated and control serum from wildtype and knock-out mice was evaluated by migration of purified human PMN, isolated by dextran sedimentation and Histopaque® centrifugation, in a transwell assay (Corning® HTS Transwell®-96 well permeable support; 3µm).Results: Adamts13 deficiency in mice was accompanied by a worse outcome of IPA infections compared to wildtype controls. Adamts13-/- mice displayed more severe signs of disease and a lethal course was observed in about 24% of animals. Compared to Adamts13-/- mice all neutropenic mice developed lethal IPA after infection, but all wild-type mice survived the disease. Besides, examination of the lungs revealed a higher fungal burden along with increased signs of acute lung injury, complement deposition and levels of pro-inflammatory cytokines in Adamts13-/- mice. Furthermore a more pronounced perivascular leukocyte infiltration was observed in histological sections indicating a dysregulated inflammatory response in Adamts13-/- mice. Importantly, the activation of neutrophil effector functions in response to TLR agonist or in PMN-mediated fungal killing of conidia or hyphae revealed no general defect in vitro. Despite enhanced complement deposition in the lungs in Adamts13-/- mice, PMN migration towards complement-activated serum revealed unaltered chemotactic properties comparing A. fumigatus -activated serum of wildtype and knock-out mice.Conclusion: In acute inflammatory processes such as fungal pneumonia the proteolytic regulation of VWF by ADAMTS-13 is an important mechanism to control PMN recruitment and outcome of infections. DisclosuresNo relevant conflicts of interest to declare.

ADAMTS13 deficiency in mice does not affect adipose tissue development

BackgroundBMI and ADAMTS13 levels are positively correlated in man. Development of obesity is associated with angiogenesis and inflammation, and increased ADAMTS13 synthesis in the liver. MethodsMale wild-type (WT) and ADAMTS13 deficient (Adamts13−/−) mice were kept on normal chow (SFD) or high fat diet (HFD) for 15weeks. ResultsHFD feeding of WT mice resulted in significantly enhanced levels of ADAMTS13 antigen and activity as compared to SFD feeding. ADAMTS13 deficiency had no significant effect on body weight gain, subcutaneous (SC) or gonadal (GN) adipose tissue mass, or on adipocyte size. In GN fat of obese (HFD) Adamts13−/− mice, adipocyte density was higher and blood vessel density lower as compared to obese WT mice. No marked effects of genotype were observed on mRNA expression of adipogenic, endothelial, inflammatory or oxidative stress markers in adipose tissue. Analysis of metabolic parameters and of glucose and insulin tolerance did not reveal significant differences between both obese genotypes, except for higher adiponectin and cholesterol levels in obese Adamts13−/− as compared to WT mice. ConclusionOur data do not support a functional role of ADAMTS13 in adiposity nor in associated angiogenesis or inflammation in mice. General significanceADAMTS13 deficiency may cause thrombotic thrombocytopenic purpura (TTP). Obesity, which is associated with enhanced ADAMTS13 levels is nevertheless considered to be an independent risk factor for TTP. To resolve this apparent contradiction, we show that ADAMTS13 does not directly promote development of adipose tissue in a mouse model.

Deficiency of ADAMTS-13 in pediatric patients with severe sepsis and impact on in-hospital mortality

BackgroundThe enzyme involved in regulating the size of vWF (von Willebrand factor) in plasma is ADAMTS-13 (A disintegrin and metalloprotease with thrombospondin type-1 motives). Deficient proteolysis of ULvWF (ultra large von Willebrand factor) due to reduced ADAMTS-13 activity results in disseminated platelet-rich thrombi in the microcirculation characteristic of thrombotic thrombocytopenic purpura. Reduced ADAMTS-13 has also been observed in severe sepsis and is associated with poor survival. We conducted this study to detect ADAMTS-13 deficiency and its impact on in-hospital mortality in pediatric patients with severe sepsis.MethodsPediatric patients diagnosed with severe sepsis were recruited for the study. Baseline clinical characteristics were noted. ADAMTS-13 antigen levels were assayed by ELISA. According to ADAMTS-13 levels, patients were grouped as deficient and non-deficient. Comparison was done with regard to some clinical and biological characteristics and in-hospital mortality between the two groups.ResultsA total of 80 patients were enrolled in the study. The median age of the patients was 3.1 years (Range: 0.1-15 years). ADAMTS-13 deficiency with levels less than 350 ng/dl was found in 65% patients. In patients with ADAMTS-13 deficiency, 75.6% had low platelets of less than 150 × 109/L. In-hospital mortality was 42.3% and 35.7% in ADAMTS-13 deficient and non-deficient group, respectively.ConclusionMajority of the pediatric patients admitted to hospital with severe sepsis exhibit ADAMTS-13 deficiency. ADAMTS-13 deficiency might play a role in sepsis-induced thrombocytopenia. More studies are needed to evaluate the role of ADAMTS-13 deficiency on in-hospital mortality.

Long-Term Outcomes of Renal Function in Patients with TTP Associated with Severe ADAMTS13 Deficiency

Abstract▪2215▪This icon denotes a clinically relevant abstract Introduction:Among survivors of TTP associated with severe ADAMTS13 deficiency, long-term outcomes other than relapse are not well documented. The recent report of persistent minor neurocognitive abnormalities attributed to subcortical microvascular thrombosis (Transfusion 2009;49:1092) suggested that other organs may also be affected by subclinical abnormalities. Therefore we documented renal function in patients in the Oklahoma TTP-HUS Registry who survived acute episodes of TTP associated with severe ADAMTS13 deficiency (activity <10%). Methods:ADAMTS13 activity has been measured in 299 of 321 (93%) patients, 1995–2010. Glomerular filtration rate (GFR) was calculated by the Chronic Kidney Disease-Epidemiology Collaboration (CKD-EPI) equation (Ann Int Med 2009;150:604). Urine protein was measured by dipstick. Patient GFRs were compared to GFRs for the US population using data from the National Health and Nutrition Examination Survey (NHANES), 1998–2006, that had been analyzed in the CKD-EPI study. Results:68 of 299 (23%) patients from the Oklahoma TTP-HUS Registry had severe ADAMTS13 deficiency. Fifty-five of the 68 (81%) patients with severe ADAMTS13 deficiency survived their initial episode of TTP. Among the 55 survivors, 48 (87%) have had ≥1 year of follow-up (median, 6.4 years; range, 1.0 – 14.9 years). The 7 patients whose follow-up was less than 1 year included 3 patients whose initial episode was within the past year; 2 with systemic lupus erythematosus who died within one year; 1 who relapsed and died at one year; 1 lost to follow-up. Sixteen (33%) of the 48 patients had 1–4 relapses. None of the 48 patients developed end stage renal disease and none developed severe chronic kidney disease (GFR <30 ml/min/1.73m2). Three of the 48 patients had chronic kidney disease with moderately decreased GFR (GFR 30–59 ml/min/1.73m2); two of these patients had hypertension and one had hypertension and diabetes prior to their initial episodes of TTP. The median GFR was 97 ml/min/1.73m2 (range, 30 – 139 ml/min/1.73m2). The GFR for the ADAMTS13 deficient TTP patients was not different from the GFR of the U.S. population (p=0.289) (Figure 1). Urine protein was measured on 34 patients (median follow-up, 6.7 years; range, 1.2–14.9 years): 32 (94%) were negative; 2 (6%) were trace, equivalent to <30 μg albumin/mg creatinine. [Display omitted] Conclusion:Renal function of TTP patients with severe ADAMTS13 deficiency who had been followed for a median of 6.4 years following recovery from their initial episode was not different from the US population. Disclosures:No relevant conflicts of interest to declare.

Clinical Characteristics of Thrombotic Thrombocytopenic Purpura with Severe ADAMTS13 Deficiency

AbstractAbstract 4666The clinical significance of ADAMTS13 activity for response to treatment, mortality rate, recurrence, and prognosis is unclear. Therefore, we investigated the characteristics of severe ADAMTS13 deficiency and evaluated its clinical significance in Thrombotic thrombocytopenic purpura (TTP). The Korean TTP Registry includes 66 patients from 13 teaching hospitals in Korea who received the diagnosis of TTP from January 2005 to December 2008. Blood samples obtained upon admission were sent for ADAMTS13 analysis (multimer analysis by sodium dodecyl sulfate electrophoresis and/or ELISA) to a central laboratory along with patient clinical information. After 6 months, patient data regarding treatment, response, and prognosis were collected on standardized report forms. Patients with severe ADAMTS13 deficiency had lower serum creatinine levels (P=0.001) and WBC counts (P=0.050) than patients with non-severe ADAMTS13 deficiency. Although severe ADAMTS13 deficiency was associated with better response rate (75% vs 53%, P=0.145), remission rate (81% vs 61%, P=0.209), and mortality rate (19% vs 31%, P=0.508) than non-severe ADAMTS13 deficiency, treatment outcomes did not differ significantly between groups. After adjusting for clinical and laboratory features, multivariate analysis did not reveal any independent risk factors for TTP-associated mortality. Patients with severe ADAMTS13 deficient had lower serum creatinine levels and WBC counts at presentation but Severe ADAMTS13 activity deficiency at TTP diagnosis does not appear to have prognostic significance. Disclosures:No relevant conflicts of interest to declare.

Distinct Mechanisms of Idiopathic and Thienopyridine-Assocaited Thrombotic Thrombocytopenia Purpura: Final Results from the Surveillance, Epidemiology, and Risk Factors for Thrombotic Thrombocytopenic Purpura (SERF-TTP) Study.

Background: Many idiopathic thrombotic thrombocytopenia purpura (TTP) patients have severe deficiency of ADAMTS13, an enzyme that cleaves ultralarge von Willebrand multimers. We recently reported that thienopyridine-associated TTP is characterized by an immunologic pathway with severe ADAMTS13 deficiency and a non-immunologic pathway with higher ADAMTS13 activity levels. We now compare findings for idiopathic and thienopyridine-associated TTP patients.Methods: Clinical findings and laboratory findings were evaluated for 51 idiopathic and 39 thienopyridine-associated TTP.Results: Clinical findings were similar between idiopathic and thienopyridine-associated TTP for both severe ADAMTS13 deficient and non-deficient patients. Differences were noted in gender and age, relapse rates, and survival.Conclusion: Among TTP patients with ADAMTS13 deficiency, relapses are frequent in idiopathic TTP patients and Rituximab may be useful, while for thienopyridine-associated TTP patients spontaneous relapse are rare as long as no re-exposure occurs. Among ADAMTS13 non-deficient patients, survival is high following therapeutic plasma exchange (TPE) for idiopathic patients but not for thienopyridine-associated TTP patients. Despite similarities, idiopathic and thienopyridine associated TTP probably have different initiating factors.ADAMTS13 activity and clinical characteristics in idiopathic and thienopyridine-associated TTPIdiopathic severe ADAMTS13 deficiency (n=29)†Thienopyridine severe ADAMTS13 deficiency (n=26)Idiopathic non-severe ADAMTS13 deficiency (n=22)†Thienopyridine non-severe ADAMTS13 deficiency (n=13)Mean Age41674760Sex (% female)79%54%86%39%Platelet count/mm3 (mean)*18,9789,26951,40935,000Platelet count <20,000/mm3*69%96%23%38%Hemoglobin (mg/dl; mean)8.58.39.08.4Creatinine (mg/dl; mean)*1.52.23.23.0Creatinine >2.5 mg/dl*11%27%48%46%30-day survival96%85%90%62%Long-term relapse*42%8%0%0%Neutralizing autoantibodies to ADAMTS13 (prior to TPE) §79%100%27%0%Neutralizing autoantibodies to ADAMTS 13 (measured at remission) §55%33%‡33%0%*p<0.05 for comparison of severe ADAMTS13 deficiency versus non-severe ADAMTS13 deficiency. †Thienopyridine-associated TTP clinical and presenting neutralizing autoantibody data was summarized from the Journal of the American College of Cardiology publication by Bennett et al. in 2007. ‡Thienopyridine-associated TTP remission autoantibody data was summarized Tsai et al, 2002, Bennett et al, 2000, and Orimo et al, 2002, and included 3 patients. §Data from average of ADAMTS13 deficient and non-deficient cohorts.

Sporadic Bloody Diarrhea-Associated Thrombotic Thrombocytopenic Purpura-Hemolytic Uremic Syndrome (TTP-HUS) in Adults in Oklahoma: Comparison to Adults with Severe Adamts13 Deficiency and to Children with Typical HUS.

The frequency, presenting features and clinical outcomes of sporadic TTP-HUS following a prodrome of bloody diarrhea in adults are not described. The Oklahoma TTP-HUS Registry enrolled 237 consecutive patients over age 18 years with their first episode of clinically diagnosed TTP from 11-13-1995 (the date of our initial ADAMTS13 measurement) to 12-31-2006 for whom plasma exchange treatment (PEX) was requested. ADAMTS13 activity was measured on 218 (92%) patients immediately before their first PEX. 16 (7%) of these 218 patients presented with a prodrome of acute bloody diarrhea. 42 (19%) patients had ADAMTS13 activity <10%. 2 patients who presented with acute bloody diarrhea had ADAMTS13 activity <10%; they are analyzed with the bloody diarrhea patients; ADAMTS13 activity in the remaining 14 patients was 40–100%. Children with typical HUS are not usually treated with PEX and therefore are not all included in the Registry. Data on children were retrieved from the Children's Hospital of Oklahoma for 2002–2006 to identify all children with typical HUS; 28 children were identified. E. coli O157:H7 infection was identified in 5 adults (of 12 tested) and 19 children (of 25 tested). No source for E. coli O157:H7 infection was identified. There were no case clusters except for one family with 2 affected children. In 2 of the adults with bloody diarrhea, a colectomy was performed before the correct diagnosis was made.Patient characteristicsAdults, bloody diarrhea prodrome (n=16)Adults, ADAMTS13 deficiency (n=40)Children, diarrhea prodrome (n=28)Age (years, median)5840*3.8**Female (%)80%81%64%Race (% white)94%53%*75%Severe neurologic abnormalities†63%45%7%**Platelet count (/μL)‡24,00010,000*34,000Hematocrit (%)‡222118**LDH (/UL) ‡141014311161Creatinine (mg/dL)‡2.71.0*3.7Acute renal failure§50%8%*57%Response to PEX (%)81%85%NADialysis (%)31%3%*57%Death (30 days)31%15%0%**Relapse (%)0% (0/10)38% (13/34)*NA* p≤0.05 for adult bloody diarrhea prodrome compared to adult ADAMTS13 deficient patients; ** p≤0.05 for adult bloody diarrhea prodrome compared to children bloody diarrhea prodrome patients; †seizure, stroke, coma, focal abnormalities anytime during the course; ‡most abnormal values on the day of diagnosis ± 7 days; median §defined by ↑ Cr ≥ 0.5 mg/dL x 2 days or Cr ≥4.0 and dialysis.Conclusions:1.TTP-HUS following bloody diarrhea is an endemic, sporadic disorder among adults that is less common and less familiar than in children.2.Distinct from children, adults with bloody diarrhea have a higher frequency of severe neurologic abnormalities and death; distinct from adults with severe ADAMTS13 deficiency, adults with bloody diarrhea are primarily white, have a higher frequency of acute renal failure, and have not relapsed.3.Although the role of PEX in the recovery of adult patients presenting with bloody diarrhea is unclear, PEX may be appropriate initial treatment since the mortality is high, many patients appear to respond, and patients with severe ADAMTS13 deficiency may also present with bloody diarrhea apparently caused by intestinal ischemia.

Clinical and Outcomes Findings for Thrombotic Thrombocytopenic Purpura among 467 Persons with Severely Versus Not Severely Deficient ADAMTS-13 Levels.

Background: Thrombotic thrombocytopenic purpura (TTP) is a rare disorder that presents with microangiopathic hemolytic anemia and thrombocytopenia, fevers, renal insufficiency and neurologic features. We reviewed clinical, laboratory, and outcome data for TTP cases with severely deficient versus non-severely deficient ADAMTS13 activity levels.Methods: Mean and median data were from the Surveillance, Epidemiology and Risk Factors for TTP (SERF-TTP) study group for idiopathic TTP cases, the Canadian Apheresis Group (CAG), and five published series (Zheng 2004, Raife 2004, Vesely 2003 (Oklahoma TTP-HUS Registry), Matsumoto 2004 (Japan Referral Center), Bennett 2007).Results: Compared to TTP cases with near-normal ADAMTS13 activity levels (n= 282), TTP cases with severe ADAMTS13-deficiency (n=185) were more likely to have severe thrombocytopenia, normal renal function and neutralizing ADAMTS13 antibodies. Severe ADAMTS13 deficient TTP cases have better overall survival after therapeutic plasma exchange (TPE) but are more likely to relapse. TTP patients with severe ADAMTS13 deficiency were primarily categorized as idiopathic or ticlopidine-associated, while TTP patients with non-severely deficient ADAMTS13 activity levels were frequently categorized as idiopathic, secondary to drugs (clopidogrel, quinine), stem cell transplantation, or cancer.Conclusions: Severe ADAMTS13 deficiency is most commonly idiopathic, has better survival following TPE, and a 35–40% spontaneous relapse rate. By contrast, non-ADAMTS13 deficient TTP cases are usually associated with an underlying disorder or external insults. Amongst this cohort, four series have 47–62% survival rates and three series, which contain mostly idiopathic cases, have 83–90% survival rates following TPE. From this, we propose that TTP may occur by three possible mechanism; ADAMTS13-deficient (antibody-mediated), an immunologic mediated pathway independent of ADAMTS13 (i.e. quinine) that is responsive to TPE, and endothelial injury related TTP that is unresponsive to TPE.Platelet count mean (x10^9/L)Creatinine mean (mg/dl)ADAMTS13 neutralizing antibodies (%)Survival %Relapse %Severe ADAMTS13 Deficiency (<10–15%)SERF-TTP (n=30)191.3839741Zheng (n=16)191.6448138Bennett (n=26)1585Oklahoma (n=18)121.8948138Raife (n=50) *131.29235Japan (n=34)3591Canada (n=11)162.482Not Severely Deficient ADAMTS13 Activity (> 15%)SERF-TTP (n=22)573.935900Raife (n=57) *442.7839Canada (n=17)574.188Zheng (n=13)403.0054Bennett (n=13)62Japan (n=66)962Oklahoma (n=94 )23473* <15% ADAMTS13 activity cutoff

Predicting Risk for Relapse in Patients Who Have Recovered from Thrombotic Thrombocytopenic Purpura (TTP).

The greatest concern for patients who have recovered from an acute episode of TTP is the risk for relapse. We have analyzed the experience of The Oklahoma TTP-HUS Registry to estimate the risk for relapse and to identify the time to relapse and factors that determine the risk for relapse. The Registry has complete follow-up data on 333 of 335 consecutive patients who had their first episode of clinically diagnosed TTP, 1989–2005. Patients who were discovered to have an alternative diagnosis for their signs of TTP, patients whose TTP followed bone marrow transplantation and patients with drug-induced TTP were not analyzed. Among the 219 remaining patients, 172 achieved a remission (defined as survival >30 days after the last plasma exchange treatment) and were at risk for relapse. Among these 172 patients, 22 (21%) of 107 patients with idiopathic TTP relapsed and 5 (8%) of 65 patients in other clinical categories (pregnancy associated, bloody diarrhea prodrome, autoimmune disease) relapsed (P<0.02). ADAMTS13 has been measured at the time of diagnosis of the first episode in 92% of consecutive patients since November 1995. Among patients who had ADAMTS13 activity <10% at the time of their initial diagnosis, 13 of 30 (43%) relapsed compared to 2 of 81 (2%) patients who had initial ADAMTS13 activity of ≥10% (P<.001). These 30 patients have been followed a median of 63 months (range, 6–124 months). Nine of the 13 patients who have relapsed have had only 1 relapse; the others have had 2–4 relapses. Nine patients had their first relapse within one year of their initial episode; the others had their first relapse within 4 years. Eleven patients followed > 4 years have never relapsed. [Display omitted] The Table compares the clinical features of the 13 ADAMTS13 deficient patients who relapsed to the 17 patients who did not relapse.Comparison between ADAMTS13 deficient patients who did and did not relapseClinical featuresRelapseNo RelapsePn=13n=17Age (years)46390.04Race (% black)62%29%0.08Sex (% men)38%0%0.01Severe neurological abnormality (%)46%35%0.55Hematocrit (%)21%21%0.82Platelets (/μL)7,00010,0000.68Creatinine (mg/dL)1.01.00.66LDH (U/L)136314340.62ADAMTS13 inhibitor (% moderate/strong)38%53%0.43Number of plasma exchanges22140.23Data are median values from the initial episode. Severe neurologic abnormalities were coma, stroke, seizure, or focal signs.CONCLUSIONS: Patients with idiopathic TTP have a greater risk for relapse than other patients. Patients who initially have severely deficient ADAMTS13 activity (<10%) have the highest risk for relapse. Most initial relapses occur within the first year following the initial episode; all occurred within 4 years. Most patients have only 1 relapse. Among patients who have ADAMTS13 deficiency (<10%), the only features that predict a greater risk for relapse are older age and male sex.

The Incidence of TTP-HUS: Racial Disparity among Patients with Severe ADAMTS13 Deficiency.

Previous studies have estimated the U.S. incidence of TTP to be 3.7/106/year, based on U.S. death certificates (Am J Hem 1995; 50:84), and 3.8/106/year, based on claims submitted to a national health insurer (Epidemiol 2004; 15:208). These methods are indirect and require extrapolation to determine incidence rates. We estimated the incidence directly from the Oklahoma TTP-HUS Registry. The Registry accrues all patients treated with plasma exchange (PE) for a clinical diagnosis of TTP or HUS (therefore excluding only children with typical HUS) in central, western, and southeastern Oklahoma since the Oklahoma Blood Institute (OBI) is the sole provider for PE in this region of 2.3 million people. Our estimates are based on patients who had their initial episode from 1/1/1996, after routine ADAMTS13 measurements began, to 6/30/2004. During these 8.5 years ADAMTS13 activity was measured in 189 (90%) of 209 consecutive patients. Prior to 1996, the number of patients accrued in the Oklahoma TTP-HUS Registry increased each year, similar to other data (JAMA 2003; 290:1351); since 1996, there has been no consistent change in the annual number of patients accrued.CategoriesIncidence (new cases/106population/year)1All patientsBlack race1Other race1CasesIncidence1CasesIncidence1CasesIncidence1All patients20910.644024.081699.40Urban211712.712927.638810.79Rural2928.821117.99818.25Idiopathic3773.922112.64563.12ADAMTS13 deficient (<5%)271.37127.22150.831Population data are from the 2000 US Census for the Oklahoma counties served by the OBI. Black race includes Black alone and in combination with one or more other races. Other race refers to all other racial designations. 2Urban or rural designations were determined by county of residence. Urban is the Oklahoma City Metropolitan Statistical Area; all other counties are rural. 3Excludes patients after BMT, pregnant/postpartum, drug-associated, bloody diarrhea prodrome, and additional or alternative diagnoses.The incidence of all patients with TTP-HUS from the Oklahoma Registry (10.64/106/year) was greater than previous reports, perhaps because of our inclusion of all patients in a defined geographic region who were treated with PE. The incidence of patients with idiopathic TTP-HUS (3.92/106/year) was similar to the previous reports for TTP. The incidence of patients with severe ADAMTS13 deficiency (<5% activity) was 1.37/106/year. For all patients with TTP-HUS the incidence of patients living in an urban area was 1.4-fold the incidence of patients living in rural areas. The rate of urban excess was greater for patients with idiopathic TTP-HUS (1.8-fold) and patients with ADAMTS13 deficiency (3.2-fold) (data not shown). Part of the urban excess may reflect better recognition of TTP-HUS because of familiarity with the Registry. However much of the urban excess can be attributed to the racial disparity that is greatest among patients with severe ADAMTS13 deficiency. Although the number of patients with severe ADAMTS13 deficiency in the Oklahoma TTP-HUS Registry is small, the incidence among the Black population was 8.7-fold the incidence among the non-Black population (95% CI, 4.1–18.5, p<0.0001). The explanation for why Black race is a risk factor for TTP is unknown, but may be related to the reasons why there is a greater prevalence of other vascular and thrombotic diseases among Blacks.

Additional Environmental and/or Genetic Factors Are Required to Trigger TTP in ADAMTS13-Deficient Mice.

Thrombotic Thrombocytopenic Purpura (TTP) is a life threatening systemic illness characterized by the formation of platelet-rich thrombi in the microcirculation and the clinical pentad of fever, hemolytic anemia, thrombocytopenia, neurological symptoms, and renal dysfunction. TTP is associated with ultra-large von Willebrand Factor multimers (UL-VWF) in the circulation due to deficiency of the ADAMTS13 metalloprotease. ADAMTS13 gene mutations account for most if not all cases of familial TTP, and autoantibodies to ADAMTS13 underlie most cases of acquired TTP. To further explore the pathogenesis of TTP in vivo, ADAMTS13 deficient mice were generated by gene targeting to remove exons 1–6 which encode most of the protease domain of ADAMTS13. Although the resulting homozygous null mice (Adamts13−/−) have lost all specific VWF-cleaving protease activity (< 1% of control), embryonic development is normal, and the null mice are born at the expected Mendelian frequency. Analysis of baseline hematologic parameters and peripheral blood smears revealed no difference between Adamts13−/− mice and wild-type littermates, with no evidence for thrombocytopenia or microangiopathic hemolytic anemia. Pathologic survey of multiple tissues revealed only normal histology and no evidence for platelet or VWF-rich thrombi in the vasculature. Despite the absence of VWF-cleaving protease activity, plasma from wild-type and ADAMTS13-deficient mice exhibited identical VWF multimer size distributions. However, VWF multimers from both wild-type and Adamts13−/− mice were observed to be considerably larger than those from normal human plasma, and equivalent in size to UL-VWF seen in plasma from familial TTP patients. Challenge of Adamts13−/− mice by injection with endotoxin, and genetic crosses to mice with markedly elevated VWF levels (CASA/Rk), failed to induce findings consistent with TTP. However, treatment with verotoxin-2 (a bacterial endothelial toxin important in the pathogenesis of the hemolytic uremic syndrome), caused thrombocytopenia in 6 of 11 Adamts13−/− mice (vs. 3 of 11 wild-type controls, p < 0.07) and mortality at 6 days in 9 of 11 Adamts13−/− mice (vs. 6 of 11 controls, p < 0.02). Examination of peripheral blood from one of the Adamts13−/− mice at 8 days following verotoxin administration demonstrated marked microangiopathic changes. In conclusion, mice with targeted disruption of the Adamts13 gene do not develop TTP spontaneously, suggesting the requirement for additional environmental triggers or genetic modifiers. Though some humans with congenital ADAMTS13 deficiency have been reported to remain asymptomatic for many years, the increased size of the baseline VWF multimer distribution in mice may indicate a higher threshold for VWF-ADAMTS13 interaction which may be protective for TTP. Our results also suggest that microbial-derived toxins, or other sources of endothelial injury, may be one of the key environmental triggers responsible for the lack of spontaneous TTP findings in the ADAMTS13-deficient mice, and possibly for the intermittent symptoms seen in humans.