Efficacy of different plasma sources in the treatment of thrombotic thrombocytopenic purpura

Plasma exchange (PE) with fresh frozen plasma (FFP) is the treatment of choice for thrombotic thrombocytopenic purpura (TTP). Since TTP patients are exposed to a large number of plasma donors, they would benefit from any additional measure of plasma safety. Several such measures have been implemented but doubts remain as to whether the new types of plasma are as effective as FFP or whether some plasma fraction may be more effective. Cryoprecipitate-poor plasma (CCP) was introduced in the therapeutics of TTP as a superior alternative to FFP. However, a clinical trial by the Canadian Apheresis Group failed to confirm the therapeutic superiority of CPP over FFP. Quarantine FFP (qFFP) is as effective as chemically modified plasma in the prevention of HIV, HBV and HCV transmission. Since qFFP has not been chemically manipulated, it must be regarded as equivalent to FFP both in terms of protein composition and therapeutic efficacy. Solvent/detergent (SD) plasma has long been used in the treatment of TTP and seems to be as effective as FFP. However, the only formal proof of efficacy consist in a small trial involving only 26 patients. Methylene blue-photoinactivated plasma (MBPIP) is used in some regions in Spain and other European countries. A recent multicentric, ‘quasi experimental’ trial involving 102 cases of idiopathic TTP has shown that MBPIP is less effective than qFFP. Patient in the MBPIP arm required twice as many PE procedures and more adjuvant therapies to achieve remission and had a higher risk of TTP recrudescence. There is only one randomized trial comparing psoralen-photoinactivated plasma to FFP. Though no difference was found in the rate of TTP remission, the trial recruited only 35 patients and was therefore severely underpowered. Levels of ADAMTS13 activity, as measured by the current laboratory assays, are similar in the various plasma sources despite some (i.e. MBPIP) are clinically less effective. In conclusion, FFP and qFFP are the plasma sources of choice for PE in TTP. CPP is probably as effective as FFP. MBPIP should be avoided because it is less effective. There is no proof that SD-plasma and psoralen-photoinactivated plasma are therapeutically equivalent to FFP. Normal levels of ADAMTS13 in therapeutic plasma seem not to be an accurate proxy of clinical effectiveness.     

Erythropoietin in thrombotic thrombocytopenic purpura and acute renal failure

Summary In this study, erythropoietin serum levels were serially determined in eight patients with acute renal failure to get a lead on the etiology of anemia in acute renal failure and to address the relationship between erythropoietin synthesis and renal excretory performance. Erythropoietin serum levels rapidly decreased after onset of acute renal failure to values of 12.8 ± 10.3 mU/ml compared to 16.8 ± 9.4 mU/ml in healthy controls. After restoration of renal function, erythropoietin levels climbed slowly in six patients (15.2 ±5.3 mU/ml), and in relation to prolonged anemia in these patients, a relative deficiency of erythropoietin could be observed. In one patient with thrombotic thrombocytopenic purpura causing acute renal failure, the decline of erythropoietin secretion was not observed, and in a phase of the disease when plasma exchange therapy was interrupted, markedly increased erythropoietin levels, up to 182 mU/ml, were detected despite the renal failure. Focusing on erythropoietin secretion in thrombotic thrombocytopenic purpura, we followed hormone synthesis in two other patients with the same disease, one of whom had mild renal insufficiency and one had normal renal function. High erythropoietin levels of up to 205 mU/ml were found in these patients, similar to the peak levels found in the patient with complete renal failure. Plasmapheresis treatment reduced erythropoietin production in all three patients with thrombotic thrombocytopenic purpura. In summary, our study indicates that in most cases of acute renal failure, erythropoietin synthesis is compromised and may contribute to the development of anemia in renal failure and aggravate the persistence of anemia after restoration of renal function. Comparing erythropoietin production in patients with acute renal failure and in those with thrombotic thrombocytopenic purpura with varying renal involvement we conclude that erythropoietin secretion is not closely linked to renal excetory performance, and that hemolysis or other stimuli in thrombotic thrombocytopenic purpura can override the decline of erythropoietin production implied by renal failure.Abbreviations ARF acute renal failure - EPO erythropoietin - TTP thrombotic thrombocytopenic purpura     

Management of thrombotic thrombocytopenic purpura

Daily therapeutic plasma exchange (TPE) transformed the historically fatal prognosis of acquired, anti-ADAMTS13 antibody-mediated thrombotic thrombocytopenic purpura (TTP), leading to the current overall survival rates of >80%. However, relapses occur in up to 40% of patients and refractory disease with fatal outcomes still occurs, typically within the first days of management. In this context, the introduction of rituximab has been the second major breakthrough in TTP management. Rituximab is now routinely recommended during the acute phase, typically in patients with a suboptimal response to treatment, and increasingly as frontline therapy, with high response rates in the following weeks. In more severe patients, salvage strategies typically include twice daily TPE, pulses of cyclophosphamide, as well as splenectomy in the more desperate cases. In this life-threatening and debilitating disease, relapses can be efficiently prevented in patients with a severe acquired ADAMTS13 deficiency and otherwise in remission with the use of rituximab. In the coming years, the TTP therapeutic landscape should be enriched by original strategies stemming from clinical experience and new agents that are currently being evaluated in large, international, clinical trials. Promising agents under evaluation include caplacizumab (an inhibitor of the glycoprotein-Ib/IX-Von-Willebrand factor axis), N-acetylcysteine, recombinant ADAMTS13, and anti-plasmocyte compounds.     

Thrombotic thrombocytopenic purpura and systemic lupus erythematosus: Successful management of a rare presentation

Thrombotic thrombocytopenic purpura (TTP) and systemic lupus erythematosus (SLE) very rarely present simultaneously and pose a diagnostic and therapeutic dilemma to the critical care team. Prompt diagnosis and management with plasma exchange and immunosuppression is life-saving. A patient critically ill with TTP and SLE, successfully managed in the acute period of illness with plasma exchange, steroids and mycophenolate mofetil is described.     

The role of human leukocyte antigen DRB1-DQB1 haplotypes in the susceptibility to acquired idiopathic thrombotic thrombocytopenic purpura

The acquired form of idiopathic thrombotic thrombocytopenic purpura (TTP) is an autoimmune disease, in which the underlying ADAMTS13-deficiency is caused by inhibitory autoantibodies against the protease. Human leukocyte antigens (HLA), responsible for antigen presentation, play an important role in the development of antibodies. The loci coding HLA DR and DQ molecules are inherited in linkage as haplotypes. The c.1858C>T polymorphism of the PTPN22 gene, which codes a protein tyrosine phosphatase important in lymphocyte activation, predisposes to a number of autoimmune diseases. We determined the HLA-DRB1-DQB1 haplotypes and the PTPN22 c.1858C>T genotypes in 75 patients with acquired idiopathic TTP and in healthy controls, in order to assess the role of these genetic factors and their interactions in the susceptibility to TTP. We found that the carrier frequencies of the DRB1¹11-DQB1¹03 and DRB1¹15-DQB1¹06 haplotypes were higher, while those of the DRB1¹07-DQB1¹02 and DRB1¹13-DQB1¹06 haplotypes were lower in TTP patients. There was no difference in the overall frequency of the PTPN22 c.1858T allele between TTP patients and controls. In conclusion, we identified four HLA-DRB1-DQB1 haplotypes associated with an increased (DRB1¹11-DQB1¹03 and DRB1¹15-DQB1¹06) or a decreased (DRB1¹07-DQB1¹02 and DRB1¹13-DQB1¹06) susceptibility to acquired idiopathic TTP.     

妊娠期特发性血小板减少性紫癜的诊断及治疗方式选择

目的 探讨妊娠期特发性血小板减少性紫癜(GITP)的临床及实验室特点,以提高这种疾病的诊断和治疗水平.方法 回顾性采集了44例GITP患者的诊断治疗经过及相关临床和实验室资料,以同期住院的148例妊娠期血小板减少症(GT),18例妊娠高血压病相关的血小板减少(GHT)以及同一年龄段的42例女性非妊娠ITP患者为对照,进行对比分析和统计学处理.结果 与GT组患者相比,GITP患者发病较早,临床出血倾向较重,初发血小板和病程中最低血小板计数均明显低于前者.GITP组患者血小板相关免疫球蛋白(PAIgG)阳性率高于GT和GHT组.GITP组剖宫产率高于GT组,与GHT组相当.3组患者术中和产后出血的发生率及新生儿Apgar评分异常的比例无显著性差异.GITP组新生儿体重与其他两组比较,差异不显著,而GHT组新生儿体重明显低于GT组.GITP组新生儿血小板减少的发生率高于其它两组,但差别无统计学意叉.GT和GHT孕妇分娩后,血小板数目多可恢复正常.GITP组分娩后也有改善,但血小板变化不如其他两组显著,常需要进一步治疗.和单纯ITP患者相比,GITP患者病情较轻,对糖皮质激素的反应率差别不大.结论 GITP患者病情较GT为重,但处理适当,对母体及新生儿影响不大.因此应早期诊断和密切监测.妊娠本身不会加重ITP 病情,但分娩也不会明显减轻症状,GITP患者分娩后多需要进一步治疗.     

Renal involvement of thrombotic thrombocytopenic purpura: Special reference to the glomeruloid structures

We report the case of a 9-year-old girl with biopsy-proven renal thrombotic microangiopathy in thrombotic thrombocytopenic purpura (TTP), with particular reference to the glomeruloid structures. The renal biopsy sample from this TTP patient revealed platelet thrombus deposition, a glomeruloid structure and aneurysm with relative sparing of the glomeruli. The glomeruloid structure displayed a proliferation of mainly capillary-sized channels lined by Factor VIII-related, antigen-positive plump endothelial cells embedded in the edematous connective tissue. These glomeruloid vessels communicated with the aneurysmal segment at the end portion of the arteriolar branch. We believe that the glomeruloid structures in TTP represent not merely organization or recanalization of thrombus but rather active angiogenesis through aneurysmal dilation in the arteriolized vessel, probably initiated by platelet agglutination.     

Dose-response relationship in the treatment of idiopathic thrombocytopenic purpura with intravenous immunoglobulin

Summary The dose-response relationship in the intravenous immunoglobulin treatment of idiopathic thrombocytopenic purpura was studied in 20 adult patients in a multicenter prospective crossover trial. The rate of response increases from 3 out of 11 (27%) to 6 out of 10 treatment periods (60%) by raising the 7S-IgG dose given on 5 consecutive days from 164.50±24.55 to 359.65±58.62 mg/kg body weight. The onset and duration of response as well as the peak platelet count were found to be independent of the doses. A long-term benefit induced by intravenous immunoglobulin treatment could be achieved in 2 out of 14 patients with chronic idiopathic thrombocytopenic purpura.Abbreviations IgG Immunoglobulin G - ITP Idiopathic thrombocytopenic purpura     

Platelet phagocytosis in the spleen of patients with idiopathic thrombocytopenic purpura (ITP)

The ultrastructure of spleen from four patients with idiopathic thrombocytopenic purpura (ITP) is studied. Platelets, with no evidence of degranulation and aggregation, leave the circulation by passing through gaps in the sinus wall in the marginal zones and the red pulp. They are then trapped by pseudopods of macrophages and are phagocytosed as whole elements. The endothelial cells lining the sinuses do not phagocytose platelets or other circulating blood cells. The degradation of these platelets in the phagolysosomes of macrophages is incomplete and results in the formation of myelinic-like figures which accumulate in large numbers in these cells. This incomplete platelet breakdown may be due to a deficiency of specific lysosomal enzymes. Erythroleucophagocytosis in ITP is normal. The results are consistent with the concept that 'self' constituents are normally and readily destroyed by autolytic enzymes. In the case of enzyme deficiency or the presence of 'foreign' antigens, including altered 'self' antigens, these enzymes become ineffective for rapid and complete degradation of the substrate. Through macrophage-lymphocyte interaction, antibody-forming cells are activated against these residual substances. These antibodies, in turn, facilitate the phagocytosis of the specific 'antigens' by macrophages. The massive platelet phagocytosis and the presence of large numbers of germinal centres in the white pulp and plasma cells in the marginal zone and red pulp suggest that the spleen is the major site of platelet destruction, as well as the site of antiplatelet antibody synthesis.     

特发性血小板减少性紫癜共刺激分子表达的研究进展

特发性血小板减少性紫癜（ITP）是一种自身免疫性疾病,其发病机制尚未完全明确,目前已证实,ITP患者体内存在T、B淋巴细胞的异常活化和B淋巴细胞依赖Th细胞辅助而产生自身抗血小板抗体。在T、B淋巴细胞相互作用和产生自身抗体的病理过程中,CD80、CD86与其配体CD28、CTLA4结合及CD40与其配体CD40L相互作用提供的共刺激信号起了重要的作用。研究表明共刺激分子过度表达有可能激活自身反应性T淋巴细胞,导致自身免疫病的发生。     

Perisinusoidal fibrosis of the liver in patients with thrombocytopenic purpura

Summary 10 patients with thrombocytopenic purpura (TP) underwent splenectomy. Eight of these patients had idiopathic TP (certain or probable). All had normal liver function tests. Liver histology of the surgical biopsy was normal with the exception of a non specific mild portal infiltration in 6 cases. On Sirius red staining the perisinusoidal network was normal in 3 cases, mildly or moderately increased in 5 cases and often associated with perivenular fibrosis. Collagen types I, III, IV, laminin and fibronectin were increased in the 8 biopsies tested. On semi-thin sections, numerous Kupffer cells were observed. Under the electron microscope, sinusoidal abnormalities were very similar in all 7 patients studied: numerous Kupffer cells containing abundant lysosomes, numerous collagen bundles in the Disse space, active endothelial cells, transformation of some perisinusoidal cells into cells with some of the characteristics of fibroblasts (increased RER) and myofibroblasts (peripheral condensations of the filamentous network), increased fragments of basement membrane-like material. In two cases there was an increase in the number of perisinusoidal cells loaded with lipids. The similarity of the lesions and the absence of other fibrogenic causes (except in 2 cases) suggest that TP may represent another group of diseases with perisinusoidal fibrosis. The aetiology of fibrosis remains unknown but platelet derived growth factor and activated macrophages may play a major role.     

Thrombotic thrombocytopenic purpura and focal segmental glomerulosclerosis associated with the use of ecstasy

Ecstasy is a drug, which causes serious side effects and sometimes it can be lethal. These effects are due to idiosyncratic reactions as a result of various stimulations in adrenergic receptors. Here we present a case of a 36-year-old male patient who was diagnosed with thrombotic thrombocytopenic purpura associated with the use of ecstasy. Plasmapheresis along with methylprednisolone treatment restores patient condition to normal.     

巨细胞病毒感染与儿童免疫性血小板减少性紫癜的关系探讨

目的探讨人巨细胞病毒（HCMV）感染与儿童免疫性血小板减少性紫癜（ITP）的关系。方法采集154例ITP患儿（ITP组）和50例健康儿童（对照组）的血清样本,用Real-time PCR检测HCMV DNA,ELISA方法检测HCMV IgM、IgG抗体;其中105例ITP患儿和50例健康对照儿童采集了尿液标本,用Real-time PCR检测HCMV DNA,并比较ITP组HCMV DNA阳性患儿与阴性患儿的血小板数量的差异。结果 ITP患儿血清HCMV DNA、HCMV IgM及IgG抗体和尿HCMV DNA阳性率均明显高于健康对照儿童,两组比较差异均有统计学意义（P〈0.01）;ITP组HCMV DNA阳性患儿的血小板数量（29.72±14.54）×109/L与阴性患儿（41.28±18.35）×109/L比较差异有统计学意义（P〈0.05）。结论儿童感染HCMV可能是发生ITP的重要致病因素之一,这对指导临床有效治疗及预防ITP的发生有着积极的意义。     

Transient disappearance of immunologic disorders and remission after intercurrent measles infections in children with chronic idiopathic thrombocytopenic purpura

In two children with chronic idiopathic thrombocytopenic purpura (ITP) a transient remission of thrombocytopenia was observed after intercurrent measles infection. Both cases were girls who had a long history of thrombocytopenia. During acute measles infection, the delayed hypersensitivity response was suppressed. Total T lymphocytes, T-cell subsets, especially OKT4 cells, the lymphoproliferative response, and interleukin-2 (IL-2) and -interferon production were decreased accompanying normalization of the OKT4/OKT8 ratio. However, OKT4 cells remained at a reasonably low level and the lymphoproliferative response stimulated with pokeweed mitogen was still in the lower normal range. Direct immunofluorescent study demonstrated that the measles antigen was present in the mononuclear cells, especially OKT4 cells. The levels of platelet-associated IgG antibody (PAIgG) and IgG circulating immune complex (CIC) were undetectable. One month later, the OKT4/OKT8 ratio lymphoproliferative response significantly increased, IL-2 and -interferon production increased, and PAIgG and IgG CIC reappeared with the relapse of thrombocytopenia. There was also a significant increase inin vitro IgG production due to the presence of patient OKT8 cells and/or OKT4 cells. However, there was no enhancement in the presence of patient B cells. This suggests that the presence of specific OKT4 helper T cells and a defect in the suppressor function of suppressor OKT8 cells contribute to an overproduction of IgG and the appearance of PAIgG accompanied by thrombocytopenia. The transient remission associated with measles infection is probably related to the effect of the virus on the helper T cells, resulting in a decrease in specific OKT4 helper T cells and normalization of the OKT4/OKT8 ratio, suppression of IL-2 and -interferon production, and platelet-associated IgG production.     

Comparison of plasma exchange with plasma infusion in the treatment of thrombotic thrombocytopenic purpura. Canadian Apheresis Study Group

BACKGROUND. Thrombotic thrombocytopenic purpura is an uncommon disease with a high mortality rate even with current treatment. The cause of the syndrome and its optimal treatment are unknown. Although both plasma exchange and plasma infusion have been useful treatments, it is not clear which is superior. In this report we describe a prospective randomized trial comparing plasma exchange with plasma infusion for the treatment of thrombotic thrombocytopenic purpura. METHODS. One hundred two patients with thrombotic thrombocytopenic purpura were randomly assigned to receive either plasma exchange or plasma infusion with fresh-frozen plasma on seven of the first nine days after entry into the trial. The total volume of plasma received by patients undergoing plasma exchange was three times that received by patients undergoing plasma infusion. All the patients also received aspirin and dipyridamole. The outcomes in the two groups were compared at the end of the first treatment cycle (day 9) and after six months. RESULTS. At the end of the first treatment cycle patients receiving plasma exchange had a higher rate of response as defined by an increase in the platelet count (24 of 51 patients) than those who received plasma infusion (13 of 51, P = 0.025). Of the 51 patients treated with plasma exchange, 2 died, whereas 8 of the 51 patients who received plasma infusion died (P = 0.035). After six months the outcome in the plasma-exchange group was still superior, with a response observed in 40 of 51 patients, whereas 25 of 51 patients in the plasma-infusion group responded (P = 0.002). Eleven patients in the plasma-exchange group died, as did 19 patients in the plasma-infusion group (P = 0.036). The overall mortality was 29 percent. CONCLUSIONS. Plasma exchange is more effective than plasma infusion in the treatment of thrombotic thrombocytopenic purpura.     

免疫性血小板减少性紫癜的发病机制与临床研究进展

免疫性血小板减少性紫癜(Immune thrombocytopenic purpura,ITP)是自身抗体介导的血小板减少综合征,自身抗原的主要成分是血小板一种或多种糖蛋白;细胞免疫也是血小板破坏的一个重要原因.目前ITP的诊断仍是临床排除性诊断,分为原发性与继发性两种.ITP治疗的目的是使患者血小板计数提高到安全水平.肾上腺糖皮质激素仍是ITP的首选药物,静脉输注丙种球蛋白(IVIg)用于控制严重出血与重度血小板减少,脾切除仍是治疗慢性ITP的主要手段.血小板生成素(TPO)类似物可能成为新的治疗方法.对成人慢性ITP患者应常规进行幽门螺杆菌(Hp)筛查,阳性患者应根除Hp.     

Platelet activity measured by plasma levels of beta-thromboglobulin and platelet factor 4 in seasonal allergic rhinitis during natural pollen exposure

Background: Upon activation, platelets release mediators with potent inflammatory properties in IgE-mediated immune responses. Moreover, the atopic state leads towards functional abnormalities of these cells. Objective: The aim of our study was to examine the degree of activation of circulating platelets in patients with seasonal allergic rhinitis (SAR) during the symptomatic period, to improve the understanding of platelet function in atopy. Subjects and Method: Plasma levels of beta-thromboglobulin (beta-TG) and platelet factor 4 (PF4) – specific markers of platelet activation were measured by enzyme-linked immunoassay in 20 patients suffering from SAR and in 15 healthy, nonatopic subjects. Results: There were no significant differences in peripheral blood platelet numbers and plasma levels of beta-TG and PF4 in SAR patients when compared with control subjects. Conclusion: It seems that increased in vivo platelet activity, assessed by measuring plasma beta-TG and PF4, may not occur during allergic inflammation that is associated with SAR.Received 25 April 2003; returned for revision 4 June 2003; accepted by A. Falus 1 July 2003     

特发性血小板减少性紫癜患者T细胞及B细胞亚群变化的研究

目的 探讨特发性血小板减少性紫癜(idiopathic thrombocytopenic purpura,ITP)患者T、B淋巴细胞亚群的变化.方法 从大理州人民医院收集ITP患者和健康者的外周血,用Sysmex血液分析仪及流式细胞术分析T细胞及B细胞亚群.结果 与健康人群比较,ITP患者CD3+T细胞百分率无明显变化,CD4+T细胞百分率降低(42.39％±12.12％,P＜0.05),CD8+T细胞百分率升高(46.93％±11.99％,P＜0.05);CD19+B细胞百分率升高(14.11％±10.28％,P＜0.05),T2B细胞百分率(34.51％±9,70％,P＜0.05)、成熟B细胞百分率(30.91％±7.12％,P＜0.05)及记忆性B细胞百分率(23.31％±8.23％,P＜0.05)增多,差异均有统计学意义.ITP患者T1 B细胞、Kappa+B细胞、Lambda+B细胞百分率与健康人差异无统计学意义.结论 ITP患者外周血T细胞亚群和B细胞亚群分布发生了变化,这种变化在ITP发病中的作用尚需进一步研究.