Clinical outcome in three patients with postpartum hemolytic uremic syndrome treated with frequent plasma exchange.

This study reviewed 3 cases of postpartum hemolytic uremic syndrome (HUS) at our hospital over a 3 year period. The 3 patients had clinical and laboratory abnormalities similar to those of 12 patients with other causes of thrombotic microangiopathy presenting during the same time span. Both groups were treated with 4-7 plasma exchange treatments/week and prednisone, 60 mg/day or its intravenous equivalent, until remission. The postpartum HUS patients had a more complicated, prolonged course; 3 of 3 required dialysis compared to 4 of 12 in the nonpostpartum group (p < 0.05), and they required more plasma exchange treatments (49 +/- 17 vs. 10 +/- 8, p = 0.0001) and a longer duration of therapy (70 +/- 31 vs. 19 +/- 17 days, p < 0.01) before remission. All postpartum HUS patients discontinued dialysis and survived whereas 4/12 nonpostpartum patients died before attaining remission. Compared to other variants of thrombotic microangiopathy, postpartum HUS requires a longer duration of therapy, but with aggressive therapy, renal and overall prognoses may be better.     

Thrombotic microangiopathy: an atypical cause of acute renal failure in patients with acute pancreatitis

Objective To report on the development and treatment of thrombotic microangiopathy, an atypical cause of acute renal failure in patients with acute pancreatitis.Design Case reports.Setting A 21-bed medical intensive care unit at an university hospital.Patients Two men with acute pancreatitis presented with acute renal failure, neurological manifestations, haemolytic anaemia and thrombocytopenia. Both patients required intensive care.Measurements Fragmented red cell count; levels of haptoglobin, amylase and lipase; serological testing for Escherichia Coli O157; computed tomography of the abdomen.Main results The patients courses were rapidly favourable after daily plasma exchange. A review of the existing medical literature was also undertaken.Conclusion As thrombotic microangiopathy may be life-threatening without administration of fresh frozen plasma or plasma exchange, physicians should consider this disease as a possible cause of acute renal failure in patients with acute pancreatitis.The authors were supported by a grant from SmithKline Beecham (France)     

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.     

Familial thrombotic microangiopathy

A family in which there were two certain and three possible cases of thrombotic microangiopathy in two generations is presented. All afflicted members studied presented with acute renal failure, and accelerated hypertension. No abnormal platelet-aggregating activity could be identified in the plasma of asymptomatic family members or in the surviving patient in remission. Although an increase in the Factor VIII: von Willebrand's factor level was found in the sole surviving patient, the multimer pattern was normal. Platelet-associated IgG level was also normal in this individual. Thus, individuals predisposed to this familial form of thrombotic microangiopathy do not have a demonstrable marker which can be implicated in the development of the disorder. Long-term study of this kindred is required to determine the factors which are important in the pathogenesis of thrombotic microangiopathy in the affected individuals.     

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.     

Schistocytic anaemia,severe thrombocytopenia,and renal dysfunction: thrombotic microangiopathy due to severe acquired ADAMTS-13 deficiency. Case 2

We present the case of a woman (age: 64 years) with acute thrombotic microangiopathy due to severe acquired ADAMTS-13 (von Willebrand factor-cleaving protease) deficiency. She was successfully treated with plasma exchange therapy and glucocorticosteroids. She relapsed seven months later, and splenectomy led to lasting remission. Pathomechanisms of thrombotic thrombocytopenic purpura, especially the role of ADAMTS-13, are discussed and therapeutic measures outlined.     

Comparison of low fixed dose versus standard-dose rituximab to treat thrombotic thrombocytopenic purpura in the acute phase and preemptively during remission

The standard dose of rituximab used in B-cell hematological malignancies, 375 mg/m² weekly, may be excessive for autoimmune conditions. Successful use of a low, fixed dose of 100−200 mg of rituximab, weekly for 4 weeks, has been reported in the literature in the treatment of autoimmune thrombotic thrombocytopenic purpura (aTTP). We retrospectively analyzed our rituximab data in aTTP over a 13-year-period for 39 patients, with the aim of comparing response and outcomes with a standard lymphoma-dose course versus a low fixed 100 mg-dose course. Compared to the standard dose (17 patients, 17 courses of 4 infusions), our patients who received a low dose (8 patients, 9 courses of 4 infusions) had a possibly lower baseline risk but did achieve a similar time to remission and number of plasma exchange procedures to remission. Preemptive low-dose courses for ADAMTS13 activity <50 % during remission (6 patients, 10 courses of 4 infusions) achieved a median peak ADAMTS13 activity of 99 %, in a median of 1 month, with no clinical relapses. Our results provide additional evidence for the efficacy of low-dose rituximab, with the benefit of much lower cost, less infusion time, and theoretically lower risk of toxicity.     

Familial Thrombotic Microangiopathy

A family in which there were two certain and three possiblecases of thrombotic microangio-pathy in two generations is presented.All afflicted members studied presented with acute renal failure,and accelerated hypertension. No abnormal platelet-aggregatingactivity could be identified in the plasma of asymptomatic familymembers or in the surviving patient in remission. Although anincrease in the Factor VIII: von Willebrand's factor level wasfound in the sole surviving patient, the multimer pattern wasnormal. Platelet-associated IgG level was also normal in thisindividual. Thus, individuals predisposed to this familial formof thrombotic microangiopathy do not have a demonstrable markerwhich can be implicated in the development of the disorder.Long-term study of this kindred is required to determine thefactors which are important in the pathogenesis of thromboticmicroangiopathy in the affected individuals.     

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.     

Complement activation in thrombotic thrombocytopenic purpura

Summary. Background: Ultra‐large von Willebrand factor and deficiency of its cleaving protease are important factors in the events leading to thrombotic microangiopathy; however, the mechanisms involved are only partly understood. Whereas pathological activation of the alternative complement pathway is linked to atypical hemolytic uremic syndrome, the role of complement activation in thrombotic thrombocytopenic purpura (TTP) is unknown. The aim of this study was to investigate whether signs of complement activation are characteristic of TTP. Patients and methods: Twenty‐three patients with TTP (18 women, median age 38 years) and 17 healthy controls (13 women, median age 38 years) were included. Complement parameters (C3, Factors H, I, B and total alternative pathway activity) together with complement activation fragments (C3a) or complexes (C1rs‐INH, C3bBbP, sC5b9) were measured by ELISA or RID. ADAMTS13 activity and anti‐ADAMTS13 inhibitory antibodies were measured by the VWF‐FRET73 assay. Results: Increased levels of C3a, and SC5b9 were observed in TTP during acute episodes, as compared with healthy controls. Decreased complement C3 levels indicative of complement consumption occurred in 15% of acute TTP patients. Significant decrease of complement activation products C3a and SC5b9 was observed during plasma exchange (PEX). The sustained presence of anti‐ADAMTS13 inhibitory antibodies in complete remission was associated with increased complement activation. Conclusion: These data document in an observational study the presence of complement activation in TTP. Further investigation is needed to determine its potential pathogenetic significance.     

A novel association of acquired ADAMTS13 inhibitor and acute dengue virus infection

BACKGROUND: Dengue is a mosquito-borne viral disease with an increasing incidence worldwide. Thrombocytopenia is a common finding in dengue virus (DV) infection; however, the underlying mechanisms remain unknown.
CASE REPORT: Here we provide the first evidence of a case of antibody formation against ADAMTS13 (ADAMTS13 inhibitor) in the course of a severe acute DV infection resulting in thrombotic microangiopathy (TMA). The patient presented with classical dengue symptoms (positive epidemiology, high fever, myalgia, predominantly in the lower limbs and lumbar region for 1 week) and, after 11 days of initial symptoms, developed TMA. Clinical and laboratorial investigation of dengue and TMA was performed.
RESULTS: The patient presented with ADAMTS13 inhibitor (IgG) during the acute phase of the disease, without anti-platelet antibodies detectable. Dengue infection had laboratorial confirmation. There were excellent clinical and laboratory responses to 11 serial plasma exchanges. Anti-ADAMTS13 inhibitor disappeared after remission of TMA and dengue resolution. No recurrence of TMA symptoms was observed after 2-year follow-up.
CONCLUSIONS: Although the real incidence of dengue-related TMA is unknown, this case provides the basis for future epidemiologic studies on acquired ADAMTS13 deficiency in DV infection. The prompt clinical recognition of this complication and early installment of specific therapy with plasma exchange are likely to improve the outcome of severe cases of dengue.     

Pulmonary tumor thrombotic microangiopathy associated with urothelial carcinoma of the urinary bladder: antemortem diagnosis by pulmonary microvascular cytology

PTTM (Pulmonary tumor thrombotic microangiopathy) is very difficult to diagnose before death. We report a case of urothelial carcinoma of the urinary bladder associated with PTTM in which an antemortem diagnosis by PMC (pulmonary microvascular cytology). PMC may represent the only chance for diagnosis and achievement of remission in PTTM.     

血栓性血小板减少性紫癜14例临床分析

为了提高对血栓性血小板减少性紫癜（TTP）的认识,对14例TTP患者的临床表现、实验室特点、治疗和转归等资料进行了回顾性分析。结果表明：在14例,TTP患者中,7例有诱发因素（妊娠4例和感染3例;1例为系统性红斑狼疮,1例为造血干细胞移植后患者）。14例患者在起病时或病程中均有不同程度的神经精神症状、Coombs试验阴性的溶血性贫血和血小板减低;8例患者有不同程度的不规则发热,以中等度发热为主;8例患者有肾脏损害,均出现蛋白尿,其中4例合并肾功能异常;在14例患者中13例血浆血管性血友病因子裂解酶（ADAMTSl3）活性明显减低（均低于10％）,其中12例患者同时存在ADAMTS13抑制物。经过血浆置换、肾上腺糖皮质激素和利妥昔单克隆抗体等治疗后,12例患者完全缓解,但8例2年复发,2例死亡。结论：TTP是由于血小板性微血栓形成而造成全身多系统、多脏器功能障碍的一种血栓性微血管病,临床过程凶险,死亡率极高,早期诊断和以血浆置换为主要手段的早期治疗可大大改善患者的预后。     

Absolute immature platelet count helps differentiate thrombotic thrombocytopenic purpura from hypertension-induced thrombotic microangiopathy

ADAMTS13 activity measurement is used in the diagnostic algorithm of thrombotic thrombocytopenic purpura (TTP), but results may not be available before initiation of therapeutic plasma exchange (TPE). The immature platelet fraction (%-IPF) and the calculated absolute immature platelet count (A-IPC) represent a test of real-time thrombopoiesis, and can be performed in most laboratories using automated analyzers. Here we report on using A-IPC kinetics to exclude idiopathic TTP in a patient with severe hypertension, thrombocytopenia, and acute renal failure, which was confirmed by a normal ADAMTS13. The complete resolution of thrombocytopenia occurred once blood pressure was controlled favoring a diagnosis of hypertension-induced thrombotic microangiopathy.     

ASFA Category IV becomes Category I: Idiopathic thrombotic thrombocytopenic purpura in a patient with presumed gemcitabine‐induced thrombotic microangiopathy

In the implementation of American Society for Apheresis national guidelines, the decision for therapeutic plasma exchange may be confounded by a clinical presentation that fits both a Category I and IV designation. We report the case of a 45‐year‐old female who presented with concern for a Category IV disorder, gemcitabine‐induced thrombotic microangiopathy, and was ultimately diagnosed with a Category I disorder, idiopathic thrombotic thrombocytopenic purpura. This case highlights the importance of ruling out idiopathic TTP by a thorough evaluation for ADAMTS13 activity and inhibitor, even when an alternate thrombotic microangiopathy diagnosis may be likely.     

Do infections provoke exacerbations and relapses of thrombotic thrombocytopenic purpura?

Several case reports have suggested an association between infections and thrombotic thrombocytopenic purpura (TTP). In Case 1, a 37-year-old female presented with TTP 6 times over 7 years, requiring 242 therapeutic plasma exchanges (TPE), for a per-course range of 4-57 TPE (median 48), and treatment durations of 4-241 days (median 71 days), largely on account of multiple exacerbations (range 0-3, median 3). Twelve of 17 (71%) of her presentations or exacerbations were associated with suspected infections, with confirmation in 9 episodes. These included pulmonary TB, CMV pneumonitis, mucocutaneous HSV, ventilator-associated or urinary tract-associated gram-negative sepsis, central line-associated staphylococcal bacteremia, and cellulitis. Except for TB, all infections occurred after splenectomy, which had been performed on day 33 of presentation 1. In Case 2, a 24-year-old female presented with TTP 3 times over 15 months. Her courses were managed with brief courses of TPE (5-11 treatments per course, median 5). Suppressed ADAMTS13 levels due to inhibitors were confirmed twice. Presentation 1 was antedated by atypical community acquired pneumonia. Presentation 3 (and possibly 2) followed prolonged, progressive, antibiotic-refractory periodontal infections ultimately requiring exodontic surgery. Our cases add to a literature that suggests that infection may be associated with exacerbations or relapses of TTP in some patients. Our patients demonstrated repeated TTP exacerbations in association with different infectious agents. A better understanding of the possible relationship between infection and clinical expression of TTP might lead to improved treatment decisions for patients with this complex illness.     

Infection as a cause of early relapse in patients recovering from thrombotic thrombocytopenic purpura

Thrombotic thrombocytopenic purpura (TTP) is a rare but severe disorder characterized by hemolytic anemia, thrombocytopenia, fever, renal failure, and neurologic manifestations. Plasma exchange is the most effective treatment for this condition reducing mortality from 90% in untreated patients to 10%. However, infections acquired during the course of therapy could lead to early relapse of TTP. In this case report, we report three patients with TTP who initially responded well to plasma exchange treatments but suffered early relapses following bacterial infections. All these patients achieved remission once appropriate antibiotic therapy was instituted although one patient eventually received four courses of rituximab. This report emphasizes the need to be vigilant for new infections especially urinary tract infections in TTP patients undergoing plasma exchange. Instituting appropriate antibiotic therapy once an infection is suspected may reduce the need for prolonged plasma exchange procedures and extended hospital stay.     

Human immunodeficiency virus associated thrombotic thrombocytopenic purpura,a clinical conundrum

HIV complicates the diagnostic and therapeutic approaches to idiopathic thrombotic thrombocytopenic purpura (TTP), prompting debate in the literature regarding the benefit of plasma exchange versus simple plasma infusion. Herein we present a case of HIV‐TTP, initially treated conservatively with plasma infusion but because of progressive neurologic decline, required urgent plasma exchange for resolution of hematologic derangements and neurologic sequelae. Based on the available literature, there appears to be a spectrum of HIV‐associated TTP disorders. Patients with advanced HIV disease and opportunistic infections who present with thrombotic microangiopathy tend to respond to simple plasma infusion, while patients with less progressive HIV disease tend to behave like those with idiopathic TTP, requiring plasma exchange rather than simple plasma infusion. This article illustrates that in patients with HIV‐TTP who do not respond to plasma infusion, early escalation to plasma exchange may help avoid life‐threatening complications such as seizures and even death.     

Idiopathic thrombocytopenic purpura during remission of thrombotic thrombocytopenic purpura

Three patients were treated empirically with anti-platelet agents, prednisone, plasmapheresis, and prostacyclin for the classical clinical syndrome of thrombotic thrombocytopenic purpura (TTP). All three patients initially responded, then relapsed after one to 13 months with a clinical picture characteristic of immunogenic thrombocytopenic purpura (ITP). At relapse, all three had thrombocytopenia without microangiopathy or other causes of thrombocytopenia. All responded to splenectomy. This complication of TTP may become more common with improved survival in TTP. Recognition may prevent inappropriate therapy.     

Clinical and morphological characteristics of lupus nephritis in systemic lupus erythematosus with antiphospholipid syndrome

AIM: To ascertain clinical and morphological features of lupus nephritis (LN) in systemic lupus erythematosus (SLE) associated with antiphospholipid syndrome (APS). MATERIAL AND METHODS: Immunological markers of SLE and APS, clinical picture, urine indices were examined in 138 patients with SLE, APS and renal dysfunction. RESULTS: LN associated with APS is characterized with marked arterial hypertension, such patients had arterial thromboses more frequently than patients with isolated LN. Patients with anticardiolipin antibodies have arteriolosclerosis, in APS - diffuse interstitial sclerosis. CONCLUSION: Renal impairment in SLE may run not only with LN but also with thrombotic microangiopathy modifying clinical symptoms and course of the disease.