MULTIPLE MYELOMA COMPLICATED BY FATAL THROMBOTIC THROMBOCYTOPENIC PURPURA (TTP) – A CASE REPORT OF AUTOPSY FINDINGS IN A TERTIARY CARE CENTRE.

Thrombotic thrombocytopenic purpura (TTP) is a syndrome characterized by microangiopathic hemolytic anemia, thrombocytopenia, neurological abnormalities, fever and renal dysfunction. Early clinical suspicion and presumptive diagnosis of TTP helps in timely initiation of treatment modalities speci?c for TTP which may prove to be lifesaving and thus augment in reducing the mortality rate of TTP which is estimated to be 80 – 90 % if left untreated. We report a case of a known case of multiple myeloma who developed TTP which proved fatal despite plasmapheresis. Signi?cant autopsy ?ndings of presence of microthrombi in the microvasculature of multiple organs is also highlighted.

Azeliragon ameliorates Alzheimer's disease via the Janus tyrosine kinase and signal transducer and activator of transcription signaling pathway

OBJECTIVES: TTP488, an antagonist of the receptor for advanced glycation end-products, was evaluated as a potential treatment for patients with mild-to-moderate Alzheimer's disease (AD). However, the mechanism underlying the protective action of TTP488 against AD has not yet been fully explored. METHODS: Healthy male rats were exposed to aberrant amyloid β (Aβ) 1-42. Lipopolysaccharide (LPS) and the NOD-like receptor family pyrin domain containing 1 (NLRP1) overexpression lentivirus were injected to activate the NLRP1 inflammasome and exacerbate AD. TTP488 was administered to reverse AD injury. Finally, tofacitinib and fludarabine were used to inhibit the activity of Janus tyrosine kinase (JAK) and signal transducer and activator of transcription (STAT) to prove the relationship between the JAK/STAT signaling pathway and TTP488. RESULTS: LPS and NLRP1 overexpression significantly increased the NLRP1 levels, reduced neurological function, and aggravated neuronal damage, as demonstrated by the impact latency time of, time spent by, and length of the platform covered by, the mice in the Morris water maze assay, Nissl staining, and immunofluorescence staining in rats with AD. CONCLUSIONS: TTP488 administration successfully reduced AD injury and reversed the aforementioned processes. Additionally, tofacitinib and fludarabine administration could further reverse AD injury after the TTP488 intervention. These results suggest a new potential mechanism underlying the TTP488-mediated alleviation of AD injury.

Plasmic score applicability for the diagnosis of thrombotic microangiopathy associated with ADAMTS13-acquired deficiency in a developing country

ABSTRACT Background: Thrombotic thrombocytopenic purpura (TTP) is a potentially fatal disease that requires early diagnosis and treatment that can be made possible by applying the PLASMIC score. This study aims to evaluate this score applicability for patients with suspected TTP in a developing country. Methods: This was a retrospective study performed at a tertiary hospital in the northeastern region of Brazil. Patients were analyzed in two groups: ADAMTS13 activity <10% and activity >10%. Patients were stratified according to the PLASMIC score, and the level of agreement between the PLASMIC score and the ADAMTS13 activity was evaluated. Results: Eight patients with thrombotic microangiopathy were included. Four patients had ADAMTS13 activity <10%, all with a PLASMIC score =6. The other four had ADAMTS13 activity >10%, all with a score <6. Based on a score =6 for presumptive diagnosis of TTP, we attained a 100% diagnostic accuracy in our sample. The PLASMIC score was also able to accurately predict response to plasma exchange and the risk of long-term unfavorable outcomes. Conclusions: The reproducibility of the PLASMIC score was quite satisfactory in our sample. It accurately discriminates between patients who had ADAMTS13 deficiency and those with normal enzyme activity, precluding the need for specific laboratory evaluation, which is not always available. This score can be useful for an early diagnosis and indicates which patients will benefit from the treatment in developing countries.

ZFP36L1 and AUF1 Induction Contribute to the Suppression of Inflammatory Mediators Expression by Globular Adiponectin via Autophagy Induction in Macrophages

Adiponectin, a hormone predominantly originated from adipose tissue, has exhibited potent anti-inflammatory properties. Accumulating evidence suggests that autophagy induction plays a crucial role in anti-inflammatory responses by adiponectin. However, underlying molecular mechanisms are still largely unknown. Association of Bcl-2 with Beclin-1, an autophagy activating protein, prevents autophagy induction. We have previously shown that adiponectin-induced autophagy activation is mediated through inhibition of interaction between Bcl-2 and Beclin-1. In the present study, we examined the molecular mechanisms by which adiponectin modulates association of Bcl-2 and Beclin-1 in macrophages. Herein, we demonstrated that globular adiponectin (gAcrp) induced increase in the expression of AUF1 and ZFP36L1, which act as mRNA destabilizing proteins, both in RAW 264.7 macrophages and primary peritoneal macrophages. In addition, gene silencing of AUF1 and ZFP36L1 caused restoration of decrease in Bcl-2 expression and Bcl-2 mRNA half-life by gAcrp, indicating crucial roles of AUF1 and ZFP36L1 induction in Bcl-2 mRNA destabilization by gAcrp. Moreover, knock-down of AUF1 and ZFP36L1 enhanced interaction of Bcl-2 with Beclin-1, and subsequently prevented gAcrp-induced autophagy activation, suggesting that AUF1 and ZFP36L1 induction mediates gAcrp-induced autophagy activation via Bcl-2 mRNA destabilization. Furthermore, suppressive effects of gAcrp on LPS-stimulated inflammatory mediators expression were prevented by gene silencing of AUF1 and ZFP36L1 in macrophages. Taken together, these results suggest that AUF1 and ZFP36L1 induction critically contributes to autophagy induction by gAcrp and are promising targets for anti-inflammatory responses by gAcrp.

Clinical characteristics and outcomes of thrombotic microangiopathy in Malaysia

BACKGROUND: Thrombotic microangiopathy (TMA) with non-deficient ADAMTS-13 (a disintegrin-like and metalloprotease with thrombospondin type 1 motif 13) outcome is unknown hence the survival analysis correlating with ADAMTS-13 activity is conducted in Malaysia. METHODS: This was a retrospective epidemiological study involving all cases of TMA from 2012–2016. RESULTS: We evaluated 243 patients with a median age of 34.2 years; 57.6% were female. Majority of the patients were Malay (62.5%), followed by Chinese (23.5%) and Indian (8.6%). The proportion of patients with thrombotic thrombocytopenic purpura (TTP) was 20.9%, 72.2% of which were acquired while 27.8% were congenital. Patients with ADAMTS-13 activity ≥5% had a four-fold higher odds of mortality compared to those with ADAMTS-13 activity <5% (odds ratio: 4.133, P=0.0425). The mortality rate was 22.6% (N=55). Most cases had secondary etiologies (42.5%), followed by acquired TTP (16.6%), atypical hemolytic uremic syndrome (HUS) or HUS (12.8%) and congenital TTP (6.4%). Patients with secondary TMA had inferior overall survival (P=0.0387). The secondary causes comprised systemic lupus erythematosus (30%), infection (29%), pregnancy (10%), transplant (8%), malignancy (6%), and drugs (3%). Transplant-associated TMA had the worst OS (P=0.0016) among the secondary causes. Plasma exchange, methylprednisolone and intravenous immunoglobulin were recorded as first-line treatments in 162 patients, while rituximab, bortezomib, vincristine, azathioprine, cyclophosphamide, cyclosporine, and tacrolimus were described in 78 patients as second-line treatment. CONCLUSION: This study showed that TMA without ADAMTS-13 deficiency yielded inferior outcomes compared to TMA with severeADAMTS-13 deficiency, although this difference was not statistically significant.

Congenital Thrombotic Thrombocytopenic Purpura: An Unusual Case of Microangiopathic Haemolytic Anaemia in a Newborn.

We present an extremely rare case of hyperbilirubinemia with rapid progression leading to bilirubin encephalopathy in term neonate. Despite early recognition and intervention, death occurred as a total serum bilirubin reached 25 mg/dl. It was a case of Coomb’s negative microangiopathic haemolytic anaemia in a newborn period which is autosomal recessive inheritance i.e. Upshaw-Schulman Syndrome. (Congenital thrombotic thrombocytopenic purpura) characterised by numerous schistocytes on peripheral blood smear, thrombocytopenia , increased reticulocyte count, increased bilirubin and LDH level. This rare disease is often misdiagnosed especially in newborn baby. So we present this case not only for its variety but also for to create more awareness among pathologist and paediatrician as treatment protocol entirely differ.

Regulatory effects of total triterpenoid of Prunella vulgarisL. on activities of ERK and TGF-β1/Smad signaling pathway in protecting hepatic fibrosis in rats / 中国药理学通报

Aim To investigate the protective effects of total triterpenoid from Prunella vulgaris L. ( TTP) on CCl4-induced hepatic fibrosis in rats and its mecha-nism. Methods Rat liver fibrosis was induced by 50% CCl4 twice a week for 12 weeks. From the 5th week, all the therapeutic groups were treated with the TTP(25, 50, 100 mg·kg-1 ) and the colchicine (0. 1 mg· kg-1 ) respectively once a day for 8 weeks. At the end of the twelfth week, the levels of ALT, AST, HA, PCⅢ, CⅣ, MDA, SOD, GSH-Px, Hyp were measured . HE and Masson staining were used to evalu-late the degree of hepatic fibrosis. The mRNA expres-sion ofα-SMA, procollagen I, Smad2, Smad3, Smad7 in liver was detected by RT-PCR, and the p-ERK pro-tein expression was evaluated by Western blot. Results Compared with the model group, TTP(25, 50, 100 mg·kg-1 ) not only reduced serum content of ALT, AST, HA, PCⅢ, CⅣand Hyp, MDA in liver tissue, improved the morphologic changes of hepatic fibrosis, but also increased SOD and GSH-Px activity. Moreo-ver, it decreased the α-SMA, procollagen I, Smad2, Smad3 mRNA expression and increased Smad7 mRNA expression in liver tissues obviously. Furthermore, TTP reduced the protein expression of p-ERK. Conclusions TTP can protect rats from CCl4-induced liver fibro-sis. The mechanism of this process may involve inhibi-ting the expression of p-ERK and interference with TGF-β1/Smad signal transduction pathway.

Twenty-one patients with thrombotic thrombocytopenic purpura:a clinical study / 中华急诊医学杂志

Objective To investigate clinical features, outcomes and laboratory findings of thrombotic thrombocytopenic purpura (TTP).Methods Patients with TTP admitted between April 2006 and January 2013 were identified by a retrospective review of records.Totally 21 patients were available,15 females and 6 males,with a median age of 46 years (ranged 18-66).The diagnostic criteria were defined by:(1)thrombocytopenia (<100 ×9 L-1)without other identifiable causes;(2)a negative Coombs'test and hemolytic anemia with schistocytes on the peripheral blood smear;and only those patients meeting the criteria for TTP,both on clinical presentation and their clinical course,were included in this study. Exclusion criteria were:(1)patients discharged or dead within 24 hours after admission;(2)patients treated with plasma exchange therapy in other hospitals;(3)medical data were incomplete;(4)cannot be followed up;and (5 )other causes of thrombotic microangiopathies.General condition of patients,etiology, clinical features,treatment and prognosis were analyzed by using the SPSS 20.0 software.P value of <0.05 was considered as significant.Results Hemolytic anemia and thrombocytopenia appeared in all of the patients. Twelve patients (57.2%) had the classical pentad manifestations of TTP (fever, thrombocytopenia,microangiopathic hemolytic anemia,symptoms of nervous system,renal injury),seven patients (33.3%)had tetrad of TTP clinical manifestations (thrombocytopenia,microangiopathic hemolytic anemia,symptoms of nervous system,fever or renal injury),and only two patients showed the triad manifestations of TTP (thrombocytopenia, microangiopathic hemolytic anemia, symptoms of nervous system).In our studies,seven patients accepted plasmapheresis,and five of them (71.4%)achieved remission.Conclusions TTP progresses quickly.Plasmapheresis is still the treatment of choice for TTP patients.Etiological treatment can help to control the conditions of patients with TTP.

Thrombotic Thrombocytopenia Purpura Refractory to Plasmapheresis Treated Successfully with Rituximab.

Thrombotic thrombocytopenia purpura (TTP) is a rare hematological disease and only 20%–30% of patients present with classic pentad. About 20% of patients with TTP are resistant to plasma exchange. We have described a 28-year-old female patient with TTP who did not have classic pentad of TTP. We ruled out all other differential diagnosis. She was refractory to plasmapheresis and was treated successfully with rituximab. It was thus concluded that on the basis of the literature review, rituximab should be considered in TTP patients who fail to respond after 7–14 days of standard treatment with daily plasmapheresis and glucocorticoids.

The evaluations of the effect of stent implantation using multimodal computed tomography in ischemic cerebrovascular patients / 中国神经精神疾病杂志

Objective To evaluate the effect of stent implantation using Multimodal CT in patients with MCA and ICA stenosis. Methods Twenty-six patients with ischemic cerebrovascular disease who received MCA or ICA stent implantation in ChongQing xinqiao Hospital were recruited. Multimodal Stroke Assessment Using CT Score (MOSAIC) was used to evaluate the Neuroimaging data before stent implantation and Alberta Stroke Program Early CT Score (ASPECTS) to evaluate the time to peak (TTP) of CTP before and after stent implantation. Results Patients were divided into 4 groups based on scores: 4 scores, 5 scores, 6 scores, and 7 scores groups. the improvement degree was increase by 31.7%±14.17%、38.6%±15.73%、43.3%±10.3%、358.6%±13.45% in 4 scores, 5 scores, 6 scores, and 7 scores groups, respectively. The paired t test demonstrated that there were a statistically significant difference among four groups(H=10.673, P <0.05). Preoperative MOSAIC score was positively correlated with the improvement of ASPECT score for TTP, with a correlation coefficient of 0.579 ( P <0.002). Conclusions Multimodal CT is a sensitive assessment for the evaluation of ischemic cerebrovascular disease and patients with a higher MOSAIC score may benefit more from stent implantation.

A Splenectomy in Plasma Exchange Refractory Thrombotic Thrombocytopenia Purpura / 대한진단검사의학회지

Thrombotic thrombocytopenic purpura (TTP) is characterized by microangiopathic hemolytic anemia, thrombocytopenia, fever, and variable abnormalities in renal function and mental status. The pathogenesis of TTP is related to an inhibitor or deficiency of the von Willebrand factor (vWF)-cleaving protease (a disintegrin and metalloprotease with thrombospondin type 1 repeats; ADAMTS-13) that cleaves the large vWF multimers. Uncleaved, large vWF molecules are present in TTP and induce thrombosis in small vessels. Even though plasma exchange was proven effective in TTP, 20-40% of the cases showed refractory to plasma exchange. We describe a 41 years old female with plasma exchange refractory TTP who was completely recovered from anemia, thrombocytopenia, and accompanying symptoms following splenectomy.

The Usefulness of the New ADAMTS-13 Activity Assay using a Fluorescence-quenching Substrate for the Diagnosis of Thrombotic Thrombocytopenic Purpura

BACKGROUND: Ever since medical professionals have recognized the important role of ADAMTS-13 in the pathogenesis of TTP, several methods to diagnosis the activity of ADAMTS-13 in the plasma of TTP patients haves been developed. However these assays have not been widely used in practice because they are cumbersome and they require several days to complete. In this study we examine the new, rapid ADAMTS-13 activity assay that uses fluorescence resonance energy transfer and we compared it with the conventional assay to determine its diagnostic advantage. METHODS: Seven TTP patients were compared with 60 healthy controls. The plasma ADAMTS-13 activity was measured using the fluorescence-quenching substrate assay method. The results were compared with the results of performing multimer analysis of SDS-agarose gel electrophoresis. RESULTS: It took only 2 hour to complete the fluorescence-quenching substrate assay. The median ADAMTS-13 activity using the fluorescence-quenching substrate was 5.9% (range: 0~29.9%) for the patient group and 99.1% (range: 74.4~143.3%) for the healthy group, respectively. The median ADAMTS-13 activity using multimer analysis of SDS-agarose gel electrophoresis was 5.6% (range: 1.6~28.8%) for the patients group and 87.7% (range: 44.1~120.9%) for the healthy group, respectively. The ADAMTS-13 activities of the two assays were well correlated (correlation coefficient: 0.69). CONCLUSION: The quantification of ADAMTS-13 activity with using the fluorescence-quenching substrate is rapid and highly specific for the diagnosis of TTP and it is expected to be used widely in the diagnosis of TTP.

Comparison of Coagulation Factor Activities of Cryoprecipitate-depleted plasma(CDP) Prepared by Two Different Methods / 대한수혈학회지

BACKGROUND: Cryoprecipitate depleted plasma(CDP) that is selectively used for therapeutic plasma exchange for the thrombotic thrombocytopenic purpura(TTP). We evaluated coagulation factor activities of CDP prepared by two different methods to use CDP as a blood component and induce a new guideline. METHODS: We studied 32 units of CDP were made from FFP collected from 16 donors. To prepare CDP, units of FFP were thawed in a 4degrees C water bath for 1 to 2 hours(rapid thawing) or thawed in a 1 to 6degrees C refrigerator for 14 to 16 hours(overnight thawing). Then CDP were refrozen within 1 hours, stored at -45degrees C and re-thawed in three weeks later. We measured prothrombin time(PT), activated partial prothrombin time(aPTT), fibrinogen, coagulation factor V, VIII, von willebrend factor(vWF) and vWF multimer of CDP at the time of preparation, after re-freezing and re-thawing. And we compared them with the results of platelet poor plasma(PPP). RESULTS: The mean volume of CDP was 129+/-12mL. We found all measured factors of CDP except factor V were significantly lower or longer than those of PPP. In the comparision of thawing method, rapid thawing CDP showed longer PT, higher activities of fibrinogen and factor VIII, lower activities of vWF than those of overnight thawing with no significant change of factor V. No significant changes were notified in all factors between the results of CDP within 1 hour of preparation and those of after re-freezing and re-thawing. CONCLUSIONS: CDP prepared by rapid thawing is more recommendable for therapeutic plasma exchange for TTP. CDP prepared by re-freezing and re-thawing can be used as a CDP just prepared from FFP.

A Case of Systemic Lupus Erythematosus Associated with Thrombotic Thrombocytopenic Purpura / 대한신장학회잡지

Although thrombotic thrombocytopenic purpura (TTP) has been described in patients with systemic lupus erythematosus (SLE), the relationship between these two diseases is controversial. It is reported that survival in SLE associated with TTP correlated with the use of plasma exchange rather than with the activity of the underlying autoimmune disease. We experienced a patient with SLE who developed TTP. The patient temporarily responded to therapy including aggressive plasmapheresis with infusion of fresh frozen plasma. Plasmapheresis could not be continued because of deterioration of renal function and pulmonary edema. TTP recurred and the patient died.