Type Of Thrombotic Microangiopathy Research Articles

#550 Characteristics of patients with aHUS who discontinued dialysis after eculizumab treatment: sub-analysis of post-marketing surveillance in Japan

Abstract Background and Aims Atypical haemolytic uraemic syndrome (aHUS), a type of thrombotic microangiopathy (TMA), is a disease accompanied by acute kidney injury which typically requires dialysis in half of the patients. Eculizumab is the first complement C5 inhibitor approved for aHUS in Japan. Early treatment initiation with eculizumab is associated with better renal outcomes, and dialysis withdrawal has been observed in some of patients on dialysis after treatment with eculizumab. However, patient characteristics relating to dialysis continuation or withdrawal after treatment with C5 inhibitors have not been investigated. Method Paediatric and adult patients with aHUS who were enrolled in Japanese post-marketing surveillance (PMS) for eculizumab and who were on dialysis at the initiation of eculizumab treatment were included in this analysis. Characteristics and clinical courses were compared in two groups: patients who discontinued dialysis within 26 weeks from initiation of eculizumab (Group A) and those who stayed on dialysis for 26 weeks (Group B). Results Among 38 patients included in this analysis, 21 patients (55%) discontinued dialysis (Group A) and 17 patients (45%) stayed on dialysis (Group B). The proportion of paediatrics/adults (7/14 vs. 2/15, P = 0.148), median age (6 vs. 8 years old, P = 0.88 and 54.5 vs. 62 years old, P = 0.47), and the proportion of patients with/without complement-related gene variants or anti-CFH antibody (9/8 vs. 6/5, P = 1.000) were comparable between the two groups. Meanwhile, the proportion of patients with hypertension at baseline was significantly lower in Group A than in Group B (6/21 vs. 11/17, P = 0.022). The median duration of dialysis before initiation of eculizumab (6.0 days vs. 17.0 days, P = 0.011) and the median time from TMA onset to eculizumab initiation (9.0 days vs. 25.0 days, P = 0.008) were significantly shorter in Group A than in Group B, respectively. In contrast, there was no significant difference in the median time from TMA onset to initiation of plasma therapy between the two groups (3.5 days vs. 8.0 days, P = 0.154). No significant difference was also observed in the median (range) duration of eculizumab treatment [75 (13-241) weeks vs. 40 (12-256) weeks, P = 0.167]. Stepwise multivariate logistic regression analysis showed that the time from TMA onset to eculizumab initiation (<15 days/≥15 days) was an independent factor associated with the withdrawal of dialysis (P = 0.013), but the existence of hypertension at baseline as a complication and patients age (paediatrics/adults) were not (P = 0.157 and P = 0.869). No patients in Group A restarted dialysis after dialysis discontinuation. Five out of 17 patients in Group B discontinued dialysis after 27 weeks; their median (range) time to dialysis withdrawal was 63 (27-184) weeks. Conclusion These results demonstrate that early initiation of C5 inhibitors can offer the chance of renal recovery and no further need for dialysis. Continuing treatment with C5 inhibitor beyond 26 weeks may also offer the chance to discontinue dialysis for some patients.

HELLP Syndrome and Differential Diagnosis with Other Thrombotic Microangiopathies in Pregnancy.

Thrombotic microangiopathies (TMAs) comprise a distinct group of diseases with different manifestations that can occur in both pediatric and adult patients. They can be hereditary or acquired, with subtle onset or a rapidly progressive course, and they are particularly known for their morbidity and mortality. Pregnancy is a high-risk time for the development of several types of thrombotic microangiopathies. The three major syndromes are hemolysis, elevated liver function tests, and low platelets (HELLP); hemolytic uremic syndrome (HUS); and thrombotic thrombocytopenic purpura (TTP). Because of their rarity, clinical information and therapeutic results related to these conditions are often obtained from case reports, small series, registries, and reviews. The collection of individual observations, the evolution of diagnostic laboratories that have identified autoimmune and/or genetic abnormalities using von Willebrand factor post-secretion processing or genetic-functional alterations in the regulation of alternative complement pathways in some of these TMAs, and, most importantly, the introduction of advanced treatments, have enabled the preservation of affected organs and improved survival rates. Although TMAs may show different etiopathogenesis routes, they all show the presence of pathological lesions, which are characterized by endothelial damage and the formation of thrombi rich in platelets at the microvascular level, as a common denominator, and thrombotic damage to microcirculation pathways induces "mechanical" (microangiopathic) hemolytic anemia, the consumption of platelets, and ischemic organ damage. In this review, we highlight the current knowledge about the diagnosis and management of these complications during pregnancy.

Спорные вопросы ведения пациенток с HELLP-синдромом

Aim. To demonstrate a clinical case of HELLP syndrome with renal damage that required the use of therapeutic plasma exchange and to review the literature data on the treatment of this condition. Key points. A clinical case of HELLP syndrome with renal dysfunction in a 19-year-old first-pregnant woman is described. The rapid development of the disease in the postpartum period required differential diagnosis of HELLP-syndrome with other types of thrombotic microangiopathy. Therapeutic plasma exchange was used in treatment. Conclusion. Differential diagnosis of HELLP-syndrome and obstetric thrombotic microangiopathy attracts the interest of obstetrician-gynecologists. In patient G. the differential diagnosis was carried out in full, according to the current clinical recommendations. Thus, effective therapy of HELLP-syndrome is possible with simultaneous influence on all pathogenetic links — activation of inflammation processes, endothelial dysfunction and coagulopathy. Keywords: severe preeclampsia, HELLP-syndrome, thrombotic microangiopathy, plasma exchange.

A validation and modification of PLASMIC score by adjusting the criteria of mean corpuscular volume and international normalized ratio.

The PLASMIC score was developed for distinguishing thrombotic thrombocytopenic purpura (TTP) from other types of thrombotic microangiopathy. However, two components of the PLASMIC score, mean corpuscular volume (MCV) and international normalized ratio (INR), showed non-significant differences between TTP and non-TTP patients in previous validations. Here, we validate the PLASMIC score and aim to modify it by adjusting the criteria of MCV and INR. A retrospective validation of suspected TTP patients was performed by reviewing electronic medical records from two medical centers in Taiwan. The performance of different modified types of the PLASMIC score was carried out. Among 50 patients included in the final analysis, 12 were diagnosed with TTP based on deficiency of ADAMTS13 activity and clinical judgement. When stratified by high (score ≥ 6) and low-intermediate risk (score < 6), the positive predictive value (PPV) of the PLASMIC score to predict TTP was 0.45 (95% confidence interval [CI]: 0.29-0.61). The area under curve (AUC) was 0.70 (95% CI: 0.56-0.82). When adjusting the criteria of the PLASMIC score from MCV < 90 fL to MCV ≥ 90 fL, the PPV increased to 0.57 (95% CI: 0.37-0.75). The AUC was 0.75 (95% CI: 0.61-0.87). When adjusting the INR from >1.5 to >1.1, the PPV increased to 0.56 (95% CI: 0.39-0.71). The AUC was 0.81 (95% CI: 0.68-0.90). MCV ≥ 90 fL and/or INR > 1.1 might be suitable modifications for PLASMIC score but should be validated in a larger sample size.

ATYPICAL HEMOLYTIC UREMIC SYNDROME: A CASE STUDY

Atypical hemolytic uremic syndrome (aHUS) is a systemic disease, a type of thrombotic microangiopathy (TMA). It is based on uncontrolled activation of the alternative complement pathway of a hereditary or acquired nature, leading to generalized thrombosis in the microvasculature. Chronic activation of the alternative complement pathway leads to the damage of endothelial cells, erythrocytes and platelets and, as a result, to thrombotic microangiopathy and systemic multiorgan damage. Currently, in roughly half of the cases, it is impossible to identify aHUS triggers. Fresh frozen plasma (FFP) is used as first-line drug to reverse the symptoms. It helps to eliminate the deficiency of self-proteins – complement factor H and complement factor I (CFH and CFI), membrane cofactor protein (MCP), and stable and labile proteins – factors of hemostasis, and to stop thrombosis in the microvasculature. FFP administration is a preparatory step before anticomplementary therapy. Disease prognosis is always serious and is associated with severe complications and high mortality. At least 6 % of patients develop multiple organ failure with generalized TMA, injury of the central nervous system, gastrointestinal tract, lungs, and kidneys. The paper describes a clinical case of a patient with aHUS.

Convalescent plasma does not provide adequate replacement of C1-Inhibitor and complements in COVID-19 patients

Abstract The rationale of Convalescent Plasma (CP) is to provide passive immunity to acutely ill COVID-19 patients. However, there are other pathologies of COVID disease that may be alleviated by CP. COVID-19 coagulopathy has been hypothesized to be a form of disseminated intravascular coagulopathy, a type of thrombotic microangiopathy. Complement activation has also been implicated in COVID-19 coagulopathy. An alternative hypothesis for additional benefits of CP is replacement of inhibitors of complements. C1-esterase inhibitor (C1-INH) is a major regulator of complement activation. We hypothesized that COVID-19 patients have decreased C1-INH and that CP transfusion would restore intravascular C1-INH and complement levels. We studied serial C1-INH and complement levels in COVID-19 patients before and after CP transfusion (200 mL) and their association with overall mortality. Methods: We identified COVID-19 patients (n=91) that received CP within the first 72 hours after admission. We collected serum and/or plasma samples at day prior and post-day 1, 3, and 10. C1 inhibitor, C3 and C4 were tested in these samples as well as in the respective CP unit given to each patient. Results: C1-INH levels day before transfusion were increased in COVID-19 patients (201.5% +/- 53%) in comparison to CP (93.2% +/- 26.2%). C1-INH transiently increased post CP transfusion and remained relatively high through day 10. No statistical difference was observed in C1-INH between survivors (n=53) and non-survivors (n=39) at any time point before or after transfusion. C3 was higher in COVID-19 patients in comparison to CP (161.5 +/-47.0 vs. 89.6 +/-15.3 mg/dL). However, C3 levels were significantly lower in non-survivors compared to survivors the day before transfusion (131.9 +/- 38.0 vs. 180.9 +/- 45.1 mg/dL, p=2.8E-06). Following transfusion, C3 levels decreased and remained steady afterwards; at all subsequent time points C3 levels were significantly lower in non-survivors compared to survivors (post-day 1: 130.6+/- 33.0 vs. 158.5 +/- 51.5 mg/dL, p=0.006; post-day 3: 116.6+/-46.5 vs. 146.2+/-42.8 mg/dL, p=0.01; post-day 10: 120.8+/-40.9 vs. 150.3+/- 45.9 mg/dL, p=0.03). C4 levels trended lower in non-survivors compared to survivors the day before transfusion (30.8+/- 15.3 vs. 37.9 +/- 16.7 mg/dL, p=0.08). The day following CP, there was a significant decrease in C4 across the entire cohort (35.1+/- 16.4 vs. 27.9+/- 18.3 mg/dL, p=0.01); subsequent levels remained steady. In conclusion, a single CP transfusion does not appear to restore C1-INH, C3 and C4 levels in hospitalized COVID-19 patients. CP transfusion is associated with a transient increase in C1-INH and decreasing C3 and C4 levels. Contrary to our hypothesis, C1-INH levels are increased in COVID-19 patients. The relationship between C1-INH and complements in COVID-19 remains to be fully elucidated. Prospective studies are needed to further delineate these relationships especially in the context of ongoing clinical trials of recombinant C1-INH in COVID-19 patients.

Features of nephropathy in various types of thrombotic microagniopathies in obstetric practice

Introduction. We assessed the features of kidney injury in patients with different types of TMA during pregnancy, taking into consideration the fact that the acute kidney injury (AKI) that occurs during pregnancy or in the early postpartum period is main- ly caused by various types of thrombotic microangiopathies (TMA), and AKI itself is a serious obstetric complication with the risk of serious complications and mortality for both mother and fetus.Objective of the study. To study the features of nephropathy in different types of pregnancy-associated TMA.Materials and methods. The study included 313 pregnant women, women in childbirth and puerperas, of which 71 women had atypical hemolytic uremic syndrome (aHUS), 124 – HELLP syndrome, 70 – varying degrees of severity of PE, a group of patients with more rare causes of TMA was also identified: TTP, CAPS and sepsis (13 patients) and 45 patients for the control group. We assessed and compared the main clinical, laboratory and instrumental data, and assessed the outcome of labour. Also, histological examination of the kidneys was performed in five patients with aHUS.Results and discussion. The results of the study have shown that the most severe manifestations of TMA in the form of target organ injury and nephropathy are usually occur in patients with aHUS, where all women developed AKI, in some cases with the formation of chronic kidney disease. In the HELLP syndrome group, AKI was recorded in 39%, but renal function quickly restored. It was found that the very fact of the presence of AKI points to a more unfavourable prognosis not only for the patients themselves, but also for the child, being the main risk factor for perinatal death. The findings of urinary sediment tests and morphological evaluation indicate that the resulting ischemia of the renal tissue in cases of aHUS, HELLP syndrome and other types of TMA can lead to tubular necrosis as compared with PE. Our results suggest that it is AKI in HELLP syndrome that is the main risk factor for perinatal death. Alas, this relationship is difficult to trace in patients with aHUS, as all of them had AKI.Conclusions. Timely recognition of the AKI phenomenon in all cases of obstetric TMA can reduce the risks for both mother and fetus. Both the prognosis for mother and the prognosis for child depend on AKI, and timely therapy can lead to a regression of AKI phenomena and the complete restoration of renal function.

Syndrome hémolytique et urémique lié au carfilzomib: évolution favorable sous éculizumab

Thrombotic microangiopathies are rare diseases characterized by an initial endothelial injury and the formation of thrombi in the microcirculation. Several types of thrombotic microangiopathies can be distinguished: the thrombotic thrombocytopenic purpura; the hemolytic and uremic syndrome, mainly “typical” following a shiga toxin-producing Escherichia coli infection or “atypical” due to a dysregulation of the alternative complement pathway; and “secondary” thrombotic microangiopathies. The use of drug treatments is reported as a frequent cause in this last category and requires stopping the offending drug. We report the case of a patient who developed “secondary” hemolytic and uremic syndrome associated with carfilzomib, a proteasome inhibitor which is used in case of multiple myeloma relapses. Besides stopping the treatment, the patient still showed signs of hemolysis and renal failure with anuria requiring hemodialysis. An eculizumab treatment was therefore initiated. The overall evolution was favorable and an improvement of the renal function promptly allowed the discontinuation of hemodialysis. We discuss the mechanisms that may activate the alternative complement pathway and the potential interest of a transient use of eculizumab in case of carfilzomib-induced hemolytic and uremic syndrome.

Pathogenesis of Atypical Hemolytic Uremic Syndrome.

Atypical hemolytic uremic syndrome (aHUS) is a type of thrombotic microangiopathy (TMA) defined by thrombocytopenia, microangiopathic hemolytic anemia, and renal failure. aHUS is caused by uncontrolled complement activation in the alternative pathway (AP). A variety of genetic defects in complement-related factors or acquired autoantibodies to the complement regulators have been found in 50 to 60% of all cases. Recently, however, the classification and diagnosis of aHUS are becoming more complicated. One reason for this is that some factors, which have not been regarded as complement-related factors, have been reported as predisposing factors for phenotypic aHUS. Given that genotype is highly correlated with the phenotype of aHUS, careful analysis of underlying genetic abnormalities or acquired factors is needed to predict the prognosis or to decide an optimal treatment for the disease. Another reason is that complement dysregulation in the AP have also been found in a part of other types of TMA such as transplantation-related TMA and pregnancy-related complication. Based on these findings, it is now time to redefine aHUS according to the genetic or acquired background of abnormalities.Here, we review the pathogeneses and the corresponding phenotypes of aHUS and complement-related TMAs.

ACUTE KIDNEY INJURY AND PREGNANCY

Acute kidney injury (AKI) in obstetrics is a serious complication of pregnancy, delivery and the postpartum period, which can have a negative impact on the outcome of pregnancy for both the mother and the fetus. Currently, in developing countries the incidence of AKI during pregnancy and in the postpartum period is 4-26% of all pregnancies, and in the economically developed regions of the world – not more than 2.8%. The frequency of obstetric AKI requiring dialysis is 1:10,000 pregnancies. The causes of kidney injury in pregnant women can be hypertensive disorders, various types of thrombotic microangiopathy (HELLP syndrome, atypical hemolytic-uremic syndrome, thrombotic thrombocytopenic purpura, catastrophic antiphospholipid syndrome), acute fatty liver of pregnancy, obstetric hemorrhages, sepsis and septic shock. The article discusses the diagnostic criteria, biomarkers and timing of development of AKI in pregnancy, the principles of treatment and prevention of this complication in obstetrics.

Atypical hemolytic uremic syndrome. Report of two cases treated with Eculizumab

Hemolytic uremic syndrome (HUS) is a type of thrombotic microangiopathy where organic damage predominates in the kidney. Atypical HUS (aHUS) is a rare disease that affects young adults and causes terminal chronic renal failure ending in dialysis, in most cases. It also recurs after kidney transplantation. aHUS is associated with genetic defects of the alternative complement pathway or its activation by other factors such as drugs, autoimmune diseases, infections, malignant hypertension and ischemia-reperfusion. We report two women aged 17 and 25 years old with catastrophic aHUS. In both cases, complement amplifying factors (drugs and infections) were added and acted on a genetic vulnerability to precipitate complement activation and produce aHUS. Both patients developed terminal renal failure and had to undergo hemodialysis. Fortunately, after a broad etiological study, it was possible to make the diagnosis of aHUS and start treatment with Eculizumab, a monoclonal antibody that changed the natural history of aHUS. It inhibits complement activity controlling microangiopathy and preventing the development of end-stage renal disease. It also improves the success rate in kidney transplantation. In the case of our patients, both discontinued dialysis after chronic treatment with Eculizumab.

Angiotensinogen and interleukin-18 as markers of chronic kidney damage in children with a history of hemolytic uremic syndrome.

Hemolytic uremic syndrome (HUS) is a type of thrombotic microangiopathy, in the course of which some patients may develop chronic kidney disease (CKD). It is clinically important to investigate the markers of a poor prognosis. The levels of angiotensinogen (AGT) and interleukin-18 (IL-18) in serum and urine were evaluated. Study was conducted in 29 children with a history of HUS. Serum and urine AGT concentration was significantly higher in children after HUS as compared to the control group. No differences depending on the type of HUS and gender were noted. The serum concentration of IL-18 in children after HUS was significantly lower, whereas in urine did not differ significantly between the sick and healthy children. A negative correlation between the concentration of AGT in serum and albuminuria in patients after HUS was detected. The results indicate that the concentration of AGT in serum and urine in children after HUS increases, which may indicate the activation of the intrarenal renin-angiotensin-aldosterone system. The statement, that AGT may be a good biomarker of CKD after acute kidney injury due to HUS requires prospective studies with follow-up from the acute phase of the disease on a larger group of patients. Reduced IL-18 serum concentration in children after HUS with no difference in its urine concentration may indicate a loss of the protective effects of this cytokine on renal function due to previously occurred HUS.

Murine systemic thrombophilia and hemolytic uremic syndrome from a factor H point mutation

AbstractComplement plays a key role in host defense, but its dysregulation can cause autologous tissue injury. Complement activation is normally controlled by regulatory proteins, including factor H (FH) in plasma and membrane cofactor protein (MCP) on the cell surface. Mutations in FH and MCP are linked to atypical hemolytic uremic syndrome, a type of thrombotic microangiopathy (TMA) that causes renal failure. We describe here that disruption of FH function on the cell surface can also lead to disseminated complement-dependent macrovascular thrombosis. By gene targeting, we introduced a point mutation (W1206R) into murine FH that impaired its interaction with host cells but did not affect its plasma complement-regulating activity. Homozygous mutant mice carrying this mutation developed renal TMA as well as systemic thrombophilia involving large blood vessels in multiple organs, including liver, lung, spleen, and kidney. Approximately 30% of mutant mice displayed symptoms of stroke and ischemic retinopathy, and 48% died prematurely. Genetic deficiency of complement C3 and factor D prevented both the systemic thrombophilia and renal TMA phenotypes. These results demonstrate a causal relationship between complement dysregulation and systemic angiopathy and suggest that complement activation may contribute to various human thrombotic disorders involving both the micro- and macrovasculature.

経過中に異なったタイプのthrombotic microangiopathy（TMA）を呈したループス腎炎の1例

症例は26歳女性，顔面と下腿の浮腫を主訴に近医受診し，血栓性血小板減少性紫斑病（thrombotic thrombocytopenic purpura：TTP）との診断のもと，血漿交換が施行され，ADAMTS13活性が上昇したにもかかわらず，血小板数が再低下し当科へ紹介となった．分析によりADAMTS13のインヒビターは存在せず，ADAMTS13の非中和抗体によるTTPであり，ループス腎炎によるネフローゼ症候群も合併していることが明らかとなった．その後も破砕赤血球の出現を伴う血小板低下が出現し，SLE（systemic lupus erythematosus）の血管内皮傷害による血栓性微小血管症（thrombotic microangiopathy：TMA）と診断した．ステロイドのパルス療法とエンドキサンパルス療法にてTMAの再燃を徐々に抑制することができ，軽快退院となった．TMAの原因を判断しながら加療することが重要と考えられた．

Effect of eculizumab and recombinant human soluble thrombomodulin combination therapy in a 7-year-old girl with atypical hemolytic uremic syndrome due to anti-factor H autoantibodies.

Atypical hemolytic uremic syndrome (aHUS), which is defined as non-Shiga toxin-associated hemolytic uremic syndrome, is a type of thrombotic microangiopathy. This syndrome presents with hemolytic anemia, thrombocytopenia, and acute kidney injury. Excessive complement activation due to genetic disorders of the complement system or production of autoantibodies to factor H (FH) causes the disease. We report a successful treatment course using eculizumab and recombinant human soluble thrombomodulin (rTMD) for a 7-year-old girl with aHUS due to anti-FH autoantibodies. Although her chief complaints were abdominal pain and loose stools, we were finally able to diagnose her with aHUS because Shiga toxin-producing Escherichia coli was not detected in her feces and a hemolytic assay analyzing FH function was positive. We administrated rTMD to our patient because of signs of disseminated intravascular coagulation. Soon after the therapeutic intervention, the platelet count began to increase and abdominal pain was moderately improved. Plasma exchange limited the efficacy of her disease. Therefore, we administered eculizumab, monoclonal humanized antibody against C5, 3weeks after admission. Platelet counts immediately increased and kidney function gradually recovered. Genetic disorders were not detected. However, anti-FH autoantibody was observed. There were no symptoms for recurrence of aHUS or kidney dysfunction for 15months, as a result of the administration of eculizumab every other week. In conclusion, combination therapy of eculizumab and rTMD was effective for an aHUS patient. This therapy may be helpful for improving the prognosis and long-term kidney function of aHUS patients.

Use of eculizumab in the treatment of a case of refractory, ADAMTS13‐deficient thrombotic thrombocytopenic purpura: additional data and clinical follow‐up

We reported last year, in this Journal, a case of thrombotic microangiopathy, defined as thrombotic thrombocytopenic purpura (TTP) by virtue of a severe deficiency in ADAMTS13 (a disintegrin and metalloproteinase with a thrombospondin type 1 motif, member 13) activity with high titre anti-ADAMTS13 autoantibodies, complicated by severe haematological, neurological and renal dysfunction, which was recalcitrant to multiple therapeutic modalities for TTP (Chapin et al, 2012). These treatments included twice-daily plasma exchange, high dose glucocorticoids, rituximab, and vincristine. Prompt haematological and organ system responses to the anti-C5 humanized monoclonal antibody eculizumab were observed, and the patient has been on continuous treatment with this agent, given as maintenance every 11–12 d, for over 18 months. Several attempts to broaden the treatment interval to the 14 d recommended by the Federal Drug Administration as part of its approval of eculizumab in the therapy of atypical haemolytic-uraemic syndrome (aHUS) result in thrombocytopenia and increases in lactate dehydrogenase (LDH) and creatinine. We also reported that a screen for complement regulatory factor mutations, using a platform offered commercially by University of Iowa researchers, failed to uncover an abnormality (Chapin et al, 2012). New data now further inform our pathophysiological understanding of the disease processes involved in this patient, and the response to treatment. First, utilizing a different assay system for ADAMTS13 activity, which was reported to completely segregate cases of acquired and hereditary TTP during periods of thrombocytopenia or decreasing platelet counts (ADAMTS13 < 10% of normal) from individuals with other types of thrombotic microangiopathy (mean 86%, standard deviation 22%) and normal subjects (mean 103%, standard deviation 12%) (Tsai & Lian, 1998; Levy et al, 2001), we found that although the patient did have inhibitors of ADAMTS13, the ADAMTS13 level was not sufficiently decreased (14%) to account for his thrombocytopenia on day 85. Furthermore, his ADAMTS13 was 103% of normal on day 120, when he continued to exhibit a propensity to recurrent thrombocytopenia that was responsive to the sole treatment of eculizumab. Second, a more comprehensive genetic sequence analysis was performed in the laboratory of Dr. Richard Smith (Maga et al, 2010). An E936D polymorphism in the complement factor H gene (CFH) was documented, although the functional significance of this mutation is unclear. Third, an enzyme-linked immunosorbant assay (ELISA), similar to one previously described by Dragon-Durey et al (2005), was used to search for anti-CFH antibodies. Such antibodies have been found in 5–10% of aHUS patients, often in association with CFHR1 genomic deletion Dragon-Durey et al (2010). In this assay we used a stringent definition of positive result for difference of the optical densities between the test wells coated with recombinant CFH and control wells coated only with buffer above the mean +3 standard deviations of healthy donor controls. Plasma samples obtained at three time points in the patient's course were assessed, in triplicate, and compared to those of 35 healthy blood donors. The patient's samples were negative for CFH antibodies on day 54 of his hospital course, which was characterized by resolution of thrombocytopenia with daily or twice daily plasma exchanges as well as treatment with rituximab and eculizumab (see Figure 1 in Chapin et al, 2012), but positive for these antibodies on days 85 and 120 when, as an outpatient, he required eculizumab to treat and prevent recurrence of thrombocytopenia and elevated LDH. We speculate that the CFH antibodies were undetectable on day 54 because plasma exchange replenished CFH and decreased the antibodies. Taken together, these results suggest that, despite the presence of ADAMTS13 inhibitors, in terms of pathophysiology, illustrated by deposition of terminal complement components in the patient's skin (see Chapin et al, 2012) and his response to anti-C5 but not plasma therapy, our patient has a coexistent disease process involving both TTP and aHUS. We propose that similar disease processes may also explain the poor response of at least a subset of TTP patients to plasma exchange therapy. The work was supported in part by a grant (R01 HL62136 to H.M. Tsai) from the Heart Lung and Blood Institute of the National Institutes of Health, USA. Drs. E. Tsai designed and performed the experiments and revised the manuscript. W. Zhou designed and performed the experiments. Drs. Chapin and Laurence provided clinical data and patient samples and revised the manuscript. Dr. H. Tsai supervised the design and performance of the experiments and drafted the manuscript. Drs. H-M Tsai and J. Laurence serve on the Advisory Board and Speaker's Bureau of Alexion Pharmaceuticals.

Update on hemolytic uremic syndrome: Diagnostic and therapeutic recommendations

Hemolytic uremic syndrome (HUS) is a rare disease. In this work the authors review the recent findings on HUS, considering the different etiologic and pathogenetic classifications. New findings in genetics and, in particular, mutations of genes that encode the complement-regulatory proteins have improved our understanding of atypical HUS. Similarly, the complement proteins are clearly involved in all types of thrombotic microangiopathy: typical HUS, atypical HUS and thrombotic thrombocytopenic purpura (TTP). Furthermore, several secondary HUS appear to be related to abnormalities in complement genes in predisposed patients. The authors highlight the therapeutic aspects of this rare disease, examining both "traditional therapy" (including plasma therapy, kidney and kidney-liver transplantation) and "new therapies". The latter include anti-Shiga-toxin antibodies and anti-C5 monoclonal antibody "eculizumab". Eculizumab has been recently launched for the treatment of the atypical HUS, but it appears to be effective in the treatment of typical HUS and in TTP. Future therapies are in phases I and II. They include anti-C5 antibodies, which are more purified, less immunogenic and absorbed orally and, anti-C3 antibodies, which are more powerful, but potentially less safe. Additionally, infusions of recombinant complement-regulatory proteins are a potential future therapy.

Acquired Idiopathic ADAMTS13 Activity Deficient Thrombotic Thrombocytopenic Purpura in a Population from Japan

Thrombotic thrombocytopenic purpura (TTP) is a type of thrombotic microangiopathy (TMA). Studies report that the majority of TTP patients present with a deficiency of ADAMTS13 activity. In a database of TMA patients in Japan identified between 1998 and 2008, 186 patients with first onset of acquired idiopathic (ai) ADAMTS13-deficient TTP (ADAMTS13 activity <5%) were diagnosed. The median age of onset of TTP in this group of patients was 54 years, 54.8% were female, 75.8% had renal involvement, 79.0% had neurologic symptoms, and 97.8% had detectable inhibitors to ADAMTS13 activity. Younger patients were less likely to present with renal or neurologic dysfunction (p<0.01), while older patients were more likely to die during the TTP hospitalization (p<0.05). Findings from this cohort in Japan differ from those reported previously from the United States, Europe, and Korea with respect to age at onset (two decades younger in the other cohort) and gender composition (60% to 100% female in the other cohort). We conclude that in one of the largest cohorts of ai-TTP with severe deficiency of ADAMTS13 activity reported to date, demographic characteristics differ in Japanese patients relative to those reported from a large Caucasian registry from Western societies. Additional studies exploring these findings are needed.

Idiopathic Noncirrhotic Intrahepatic Portal Hypertension is Associated with Sustained ADAMTS13 Deficiency

ADAMTS13 deficiency leading to excess ultralarge von Willebrand factor (VWF) multimers and platelet clumping is typically found in thrombotic thrombocytopenic purpura (a type of thrombotic microangiopathy). Idiopathic noncirrhotic intrahepatic portal hypertension (NCIPH) is a microangiopathy of portal venules associated with significant thrombocytopenia and predisposing gut disorders. To determine whether the portal microangiopathy in NCIPH is associated with ADAMTS13 deficiency. Plasma levels of ADAMTS13, anti-ADAMTS13 antibodies, and VWF were compared between cases (NCIPH patients) and controls (with chronic liver diseases of other etiology) matched for severity of liver dysfunction. Eighteen NCIPH patients [median (range) MELD score 12 (7-25)] and 25 controls [MELD score 11 (4-26)] were studied. ADAMTS13 activity was reduced in all 18 NCIPH patients and significantly lower than controls (median, IQR: 12.5%, 5-25% and 59.0%, 44-84%, respectively, P<0.0001) [normal range for plasma ADAMTS13 activity (55-160%)]. ADAMTS13 activity was <5% in 5/18 NCIPH patients (28%) and 0/25 controls (P=0.009). ADAMTS13 antigen levels were also decreased. Sustained low ADAMTS13 levels were seen in four NCIPH patients over 6 weeks to 11 months (highest ADAMTS13 level in each patient: <5%, 6%, 6%, and 25%), despite two patients having MELD score 12. Although nine cases had low titer anti-ADAMTS13 antibodies, there was no significant difference between cases and controls. Abnormally large VWF multimers were observed in 4/11 NCIPH patients (36%) and in 0/22 controls (P=0.008). Sustained deficiency of ADAMTS13 appears characteristic of NCIPH, irrespective of severity of liver disease.

Thrombotic Microangiopathies: Multimers, Metalloprotease, and Beyond

The pathophysiology of various types of thrombotic microangiopathies is coming progressively into focus. Therapeutic advances are likely to follow at a quickening pace. This discussion focuses on thrombotic thrombocytopenic purpura (TTP), the hemolytic-uremic syndrome (HUS), thrombotic microangiopathies associated with transplantation-immunosuppression or anti-angiogenesis therapy, and the preeclampsia/hemolysis-elevated liver enzymes and low platelets syndrome (HELLP).