Extracorporeal plasma treatment in thrombotic thrombocytopenic purpura and hemolytic uremic syndrome: a review.

This review summarizes the state of the art of apheresis in hemolytic uremic syndrome (HUS) and in thrombotic thrombocytopenic purpura (TTP). Both entities are characterized by thrombotic microangiopathy, hemolytic anemia, and thrombocytopenia. While HUS often presents with renal insufficiency, cerebral involvement is more common in TTP. Recently, in TTP, a primary or secondary lack of activity of a von Willebrand factor (vWF) degrading enzyme was made responsible for the presence of unusually large vWF multimers causing platelet aggregation and thrombus formation in the microvasculature. In contrast, in familial HUS, a factor H deficiency with uninhibited complement activation seems to play a role. Therapeutic plasma exchange (TPE) using fresh frozen plasma or cryosupernatant as the substitution fluid is indicated in acute TTP and atypical HUS without antecedent diarrhea. As a rule, it will show good effectiveness, especially in the former entity. HUS in pregnancy should be treated by instant delivery whereas postpartum HUS may resolve using protracted courses of TPE. In contrast, in thrombotic microangiopathy after bone marrow transplantation as well as in HUS due to cancer, mitomycin C, or after renal transplantation, TPE is of questionable value and indicated only as a last resort treatment.     

血栓性微血管病诊治进展

血栓性微血管病(thrombotic microangiopathy,TMA)是一组急性临床病理综合征.经典的血栓性微血管病主要指溶血尿毒综合征(hemolytic uremic syndrome,HUS)及血栓性血小板减少性紫癜(thrombotic thrombocytopenic purpura,TTP).虽然血栓性微血管病在病理学上表现类似,但其发病机制复杂,诊断和治疗手段上也不尽一致.近年来随着对其发病机制的深入研究和理解,其治疗方案也有了日新月异的进步,预后大为改善.本文拟就血栓性微血管病的诊断和治疗的最新进展作一综述.     

The management of idiopathic thrombotic microangiopathy. Changing trends.

Thrombotic microangiopathy, including the two related syndromes thrombotic thrombocytopenic purpura and hemolytic-uremic syndrome, is a rare and severe multisystem disorder, due to widespread deposition of intravascular microthrombi consisting mainly of platelets, with subsequent consumption thrombocytopenia, microangiopathic hemolytic anemia, renal abnormalities, and neurologic disturbances. The epidemic, verotoxin-induced hemolytic-uremic syndrome, typically associated with prodromal diarrhea, mainly affects young children in small outbreaks. By contrast, idiopathic thrombotic microangiopathy generally affects adults in a sporadic form; it has a more devastating course and a less favourable outcome. Over 90% of the reported cases in the adult, when untreated, have progressed to death within three months of diagnosis. Since the introduction of plasma exchange, a dramatic change in the prognosis of the disease has taken place, although the mortality rate still remains considerable. Indeed, improved survival is the most striking feature of adult thrombotic microangiopathy compared to some decades ago. In the present article we will focus on the evolving concepts able to exert a considerable impact in the management of the adult idiopathic form of thrombotic microangiopathy.     

移植相关血栓性微血管病的研究进展

移植相关血栓性微血管病(TA-TMA),是一类以微血管病性溶血性贫血、肾功能不全和神经系统异常为主要特征的造血干细胞移植(HSCT)并发症.TA TMA发病机制可能与移植预处理、病原微生物感染、钙调磷酸酶及雷帕霉素靶蛋白(mTOR)抑制剂、移植物抗宿主病(GVHD)、细胞因子、补体及中性粒细胞胞外陷阱(NET)等多种因素相关.临床对TA-TMA的诊断标准,目前仍局限于有创性较大的组织病理学诊断,缺乏有创性较小的特异性生物标志物诊断手段.目前,治疗性血浆置换、GVHD预防药物的调整、去纤苷、利妥昔单抗及依库珠单抗等,可能是治疗TA-TMA的有效手段.随着对TA-TMA发病机制研究的深入,制定其标准诊断和治疗方案正受到国内外广泛关注.笔者拟就TA-TMA的研究进展综述如下.     

Various clinical manifestations in patients with thrombotic microangiopathy.

BACKGROUND: Thrombotic microangiopathy (TM) is characterized by thrombocytopenia and microangiopathic hemolytic anemia in association with diffuse microthrombi in the arteriolar capillaries of various organs. Its clinical manifestation is protean, and a few well-defined clinical syndromes have been recognized. A clear understanding of the consequence of TM is needed to appreciate the unusual clinical syndromes due to atypical presentation of thrombotic thrombocytopenic purpura (TTP). METHODS: The medical records of patients with known diagnoses of TTP, hemolytic uremic syndrome (HUS), and the syndrome in which hemolysis, elevated liver enzymes, and low platelet count are found in association with pregnancy were examined retrospectively from 1981 to 1994 and prospectively from 1995 to 2000. Various thrombotic microangiopathic presentations were identified in these patients. Their response to exchange plasmapheresis was evaluated, and their clinical outcome was determined. RESULTS: A total of 74 patients were diagnosed with TM. Among these patients, several well-defined thrombotic microangiopathic presentations were identified. These presentations included TTP in 57 patients, acute respiratory distress syndrome (ARDS) in 13 patients, HUS in 9 patients, the syndrome in which hemolysis, elevated liver enzymes, and low platelet count are found in association with pregnancy in 9 patients, peripheral digit ischemic syndrome (PDIS) in 6 patients, pancreatitis in 3 patients, hepatitis in 3 patients, and nonocclusive mesenteric ischemia (NOMI) in 2 patients. Exchange plasmapheresis was an effective treatment, with a response rate of 79%. A poor prognosis was evident when ARDS was present, with an overall survival rate of 46%. CONCLUSION: Traditionally, TTP and HUS are considered the main entities of TM. It is evident that other manifestations of TM, if unrecognized in a timely fashion, can lead to fatality. The understanding of the pathophysiologic consequences of TM and the recognition of its atypical presentations are essential to achieve favorable outcomes in patients with this life-threatening disease.     

1例狼疮性肾炎合并血栓性微血管病患者的护理

总结1例狼疮性肾炎合并血栓性微血管病患者的护理。护理要点包括：密切观察患者生命体征的变化;做好血浆置换及连续性血液净化治疗的护理;做好利妥昔单抗的用药护理、预防院内感染及心理护理等。经上述措施的实施,住院45天后患者病情好转出院。     

Posttransplant thrombotic microangiopathy: sensitivity of proposed new diagnostic criteria

BACKGROUND: Objective diagnosis of transplantation-associated thrombotic microangiopathy (TA-TMA) has traditionally been difficult due to the multiple potential etiologies of thrombocytopenia and red blood cell fragmentation occurring after allogeneic hematopoietic stem cell transplantation (SCT). To attempt to address this issue of diagnostic uncertainty, two new diagnostic criteria for TA-TMA have recently been proposed: the Bone Marrow Transplant Clinical Trials Network (BMT-CTN) and the International Working Group (IWG) criteria. However, both newly proposed criteria are yet to be clinically validated.
STUDY DESIGN AND METHODS: All 15 cases of TA-TMA previously diagnosed at the authors' institution between December 2001 and March 2008 were retrospectively reclassified under the newly proposed BMT-CTN and IWG criteria.
RESULTS: Potential diagnostic pitfalls were identified in both the BMT-CTN and the IWG TA-TMA criteria. The main limitation of the BMT-CTN criteria appeared to be need for concurrent renal and/or neurologic dysfunction to be manifest at TA-TMA diagnosis, which was present in only 73% of our patient cohort. For the IWG criteria, the main limitation to TA-TMA diagnosis appeared to be the requirement for schistocytosis of more than 4%, which was present in only 27% of these patients.
CONCLUSION: Our experience suggests that potentially significant diagnostic pitfalls remain with both recently proposed TA-TMA diagnostic criteria, pitfalls that are likely to limit the diagnostic sensitivity of both. It is recommended that further clinical correlation of both the BMT-CTN and the IWG criteria be undertaken before either is routinely adapted into SCT practice.     

Design of the prospective randomized study for the treatment of patients with thrombotic microangiopathy. PRODROMI Study Group.

In thrombotic microangiopathies hemolytic uremic syndrome and thrombocytopenic purpura, plasma exchange (PE) therapy using fresh frozen plasma is standard. In almost 20% of the patients, however, this approach is ineffective. This prospective, randomized study for the treatment of patients with thrombotic microangiopathies (PRODROMI) compares PE with fresh frozen plasma (A) and cryosupernatant (B). The participating centers were the University Clinics of Freiburg, Hamburg, Düsseldorf, Essen, G?ttingen, Mannheim, Ulm, Jena, Tübingen, Würzburg, Kreiskrankenhaus Offenburg, St?dt Klinikum Karlsruhe, and Horst-Schmidt Kliniken in Wiesbaden, Germany. Patients (18 to 80 years) were diagnosed by the individual centers based on clinical and laboratory findings (thrombocyte/fragmentocyte count, hemoglobin, serum creatinine, haptoglobin and lactate dehydrogenase levels; negative Coombs-test is obligatory). HIV infection, bone marrow, or solid organ transplantation were exclusion criteria. After written consent, patients were randomized in the A or B group. All patients received 1.5 mg/kg methylprednisolone as a basic therapy. The first PE always was performed with fresh frozen plasma (50 ml/kg). A minimum of 5 and a maximum of 10 PEs were required. Thrombocyte count above 150,000/microl was considered to be a successful therapy. Treatment failure was defined as not responding to 10 PE with a thrombocyte count above 150,000/microl or a fall below this value within 30 days after stopping PE. Patients with clinical and laboratory signs of thrombotic microangiopathy occurring later than 30 days after having stopped PE were considered to have a relapse. Primary endpoints were survival, intensity of required PE sessions (duration, volume, and number), and relapse rate. Follow-up of clinical outcome was 2 years; von Willebrand Factor (vWF), vWF-cleaving-protease activity, and Factor H were determined.     

Infection frequently triggers thrombotic microangiopathy in patients with preexisting risk factors: A single‐institution experience

Thrombotic microangiopathies are rare conditions characterized by microangiopathic hemolytic anemia, microthrombi, and multiorgan insult. The disorders, which include hemolytic uremic syndrome and thrombotic thrombocytopenic purpura, are often acute and life threatening. We report a retrospective analysis of 65 patients presenting to our institution from 1997 to 2008 with all forms of thrombotic microangiopathy. Therapeutic plasma exchange was a requirement for analysis and 65 patients were referred to our institution; 66% of patients were female and median age at presentation was 52 years. Bacterial infection was the most commonly identified etiologic factor and in the multivariate model was the only significant variable associated with survival outcome (odds ratio 5.1, 95% confidence interval, 1.2–21.7). As infection can be considered a common trigger event for thrombotic microangiopathy, patients with hepatobiliary sepsis may benefit from elective cholecystectomy. We conclude that bacterial infection frequently triggers TTP and other thrombotic microangiopathies in patients with preexisting risk factors and propose a model for the development of these syndromes. © J. Clin. Apheresis 2010. © 2010 Wiley‐Liss, Inc.     

血浆置换治疗不同病因血栓性微血管病的效果观察

目的 分析不同病因的血栓性微血管病（TMA）患者的临床特点,血浆置换（PE）治疗效果及预后,以提高对这一组疾病及其治疗的认识.方法 回顾性分析作者医院2005-2013年间收治的经过血浆置换治疗的血栓性微血管病患者的临床表现、实验室检查、治疗、随访及预后等资料.结果 共22例患者,男：女比为9：13,平均年龄为33.1±13.8岁.2例为原发性TMA,病程呈良性,PE治疗效果好,长期存活率高;3例为系统性红斑狼疮相关TMA,肾脏损害重,需要肾脏替代治疗,PE治疗完全缓解率及存活率为33.3％.17例为造血干细胞移植术后TMA,肾脏损害相对轻,均不需要肾脏替代治疗,对PE总体反应率41.1％,完全缓解率为17.6％,但长期预后差,存活率仅为11.8％.结论 血浆置换治疗对原发TMA治疗效果最好;继发于系统性红斑狼疮及造血干细胞移植的TMA治疗效果不佳.原发者PE可作为一线治疗;对常规治疗方法无效的继发性TMA,PE可作为二线治疗推荐.     

Hematocrit and C-reactive protein predict treatment response times in ADAMTS13-deficient thrombotic microangiopathy

Thrombotic microangiopathy (TMA) syndromes are a heterogeneous group of microvascular syndromes that are typically treated with plasma exchange and other adjunctive therapies. Important pathogenic factors, such as ADAMTS13 deficiency, define distinct subsets of TMA. New treatments for TMA are being explored that are hypothesized to bring about remission more quickly. However, the existing factors that influence response to treatment time are poorly understood. We hypothesized that common laboratory parameters available at the time of treatment initiation might correlate with the number of days of plasma exchange required to induce remission. We therefore retrospectively compared pretreatment platelet counts, hematocrit levels, and C-reactive protein (CRP) levels to the number of days of plasma exchange treatment in 27 ADAMTS13-deficient TMA patients and 25 non-ADAMTS13-deficient patients that achieved remission. Using quantile regression analysis, we observed that in ADAMTS13-deficient patients, higher initial hematocrit levels significantly correlated with shorter treatment response times. In addition, for ADAMTS13-deficient patients, elevated levels of CRP correlated directly with longer response times. Higher platelet counts were associated with a nonsignificant trend toward shorter response times. In non-ADAMTS13-deficient TMA patients no significant correlations were observed. Our results suggest that when conducting clinical trials of adjunctive treatments for TMA, clinical data, including ADAMTS13 levels, pretreatment hematocrit levels, and CRP levels may be informative in interpreting response to treatment times.     

Television programming and disability: a ten year span

Television programming covering disability over a ten year span, 1967-68 and 1977-78, was studied to determine similarities and differences. Variables identified for comparisons included network, program type, disability, time slot, and length of programming. The largest frequency of programs occurred on NBC in 1968. However, in 1978 the largest frequency occurred on the Public Broadcasting System. This can be partially explained by the increased numbers of programs on PBS overall and their traditional concern with public interest and service programming. The commercial networks historically have been in the business of entertaining and portray disability more so in that fashion. Movies head the list in 1968. However, in 1978, dramatic series and children's programming head the list followed by news documentaries and telethon. Paraplegia was the most frequent disability portrayed in 1968 followed by mental illness, drug addiction and emotional disability. In 1978 mental illness headed the list followed by alcoholism, emotional disability and physically handicapped. Paraplegia in 1968 can be accounted for by the program "Ironside" that featured a paraplegic detective. Mental illness and emotional disturbance seem to be consistent targets over the decade for popular programming in prime time.