Classic Thrombotic Thrombocytopenic Purpura Research Articles

Metabolism-mediated thrombotic microangiopathy and B12.

Thrombotic microangiopathies (TMAs) are a group of life-threatening conditions requiring urgent management and characterized by a clinical triad of microangiopathic hemolytic anemia, thrombocytopenia, and ischemic tissue injury. Severe vitamin B12 (Cobalamin-Cbl) deficiency or defective cobalamin metabolism, particularly defects in intracellular B12 metabolism, may lead to a TMA-like picture. The latter has been termed metabolism-mediated TMA (MM-TMA). This confusing picture is mediated partly by ineffective erythropoiesis with significant red cell fragmentation resulting in a hemolytic pattern, coupled with reduced platelet production and endothelial injury with organ damage resulting from accumulated toxic byproducts of B12 dysmetabolism. However, unlike in classic thrombotic thrombocytopenic purpura, where therapeutic plasma exchange has to be initiated promptly, cases of MM-TMA can be treated, if diagnosed properly, with adequate B12 replacement.

Clinical characteristics and outcomes of adult patients with acquired thrombotic thrombocytopenic purpura: a single center retrospective study.

Thrombotic thrombocytopenic purpura (TTP) is a rare disease and a potentially life-threatening thrombotic microangiopathy. Although the diagnostic and therapeutic techniques have improved, it is still difficult for clinicians to identify early due to different initial clinical manifestations and the incidence and survival rate are reported inconsistently. This study investigated the clinical characteristics, treatment strategies, and treatment outcomes of adult patients with acquired TTP. A retrospective analysis of 55 patients (35 females and 20 males) treated for acquired TTP from January 1, 2013 to December 31, 2017 was conducted. The analysis included clinical manifestations at onset, treatment efficacy measures, survival, cause of death, and the APACHE II (Acute Physiology and Chronic Health Evaluation II) and SOFA (sequential organ failure assessment) scores. At onset, in addition to thrombocytopenia and hemolysis, 50 patients (90.91%) presented with neurological abnormalities, but only 19 (34.55%) showed the classic TTP pentad of symptoms. The overall mortality rate was 34.55%. Plasma exchange (PEX) was performed in 49 patients. The most effective treatment was PEX with a normal dose of corticosteroid and rituximab which showed a response rate of 81.25%. The main cause of death was cerebral hemorrhage. The APACHE II and SOFA scores were higher in non-survivors compared to survivors (APACHE II: 20.12±7.83 vs. 11.50±4.49, P<0.05; SOFA: 12.06±3.27 vs. 7.74±2.10, P<0.05). Non-survivors had higher levels of lactic dehydrogenase (LDH; 1,646.94±1,269.48 vs. 942.76±740.58 IU/L, P=0.015), and higher numbers of schistocytes (6.18%±4.69% vs. 3.44%±3.13%, P=0.035) compared to survivors. TTP progressed rapidly, and its clinical manifestations varied between patients. The diagnosis depended on the clinical features and laboratory tests. Combination therapy with PEX, immunosuppressive therapy, and rituximab may be useful. Higher APACHE II and SOFA scores, higher LDH levels, and a greater degree of schistocytosis were associated with the severity and outcome of TTP.

Pathophysiology of Thrombotic Thrombocytopenia Purpura

This review describes classical thrombotic thrombocytopenic purpura (TTP), discusses the pathogenesis of acquired and congenital TTP, describes clinical and laboratory manifestations observed in patients, and lists treatment options for managing patients with TTP. TTP is a rare hematologic disorder characterized by thrombocytopenia and microangiopathic hemolytic anemia (MAHA). It results from a congenital or acquired deficiency of ADAMTS13 in plasma. Most cases are due to an autoimmune mechanism that interferes with ADAMTS13, however rare inherited forms of TTP have been described (Upshaw-Shulman syndrome, USS). It is still considered a life-threatening disease with a mortality rate of 10-20%. Severe deficiency of ADAMTS13 (

Prospective Evaluation of the Pre-, Intra-, and Postoperative Kinetics of ADAMTS-13, von Willebrand Factor, and Interleukin-6 in Vascular Surgery.

Postoperative thrombotic thrombocytopenic purpura (TTP) shows clinical presentation similar to classical TTP, whereas exact pathophysiological contexts remain unexplained. In this study, we investigated intraoperative and postoperative changes in ADAMTS-13 (a disintegrin and metalloprotease with thrombospondin type 1 motifs, member 13), von Willebrand factor (VWF), large VWF multimers, and interleukin-6 (IL-6) in vascular surgery patients. The objective was to compare the impact of endovascular, peripheral, and aortic surgery on target parameters which are supposed to play a role in surgery-associated TTP. A total of 93 vascular surgery patients were included and divided into 4 groups according to the specific type of intervention they underwent. Blood samples were taken preoperatively, intraoperatively, and postoperatively on days 2 and 4. The ADAMTS-13 activity decreased significantly in 3 of the 4 groups during surgery (from median 81% to 49%, P < .001, in the group undergoing aortoiliacal interventions), whereas the percentage of large VWF multimers increased in all groups of patients. von Willebrand factor antigen increased significantly in all groups on postoperative day 2 and IL-6 increased significantly in the intraoperative and early postoperative period. There was no significant correlation between the intraoperative decrease in ADAMTS-13 and the increase in VWF or IL-6. No patient in this study showed clinical picture of TTP; the precise cause and clinical significance of moderately reduced ADAMTS-13 activity in the perioperative setting have not yet been definitely determined.

Thrombotic Thrombocytopenic Purpura: A Case Series from a Tertiary Care Centre in Northern India

Abstract: Thrombotic thrombocytopenic purpura is a medical emergency with varied clinical manifestations. High index of suspicion with careful evaluation of thrombocytopenia and hemolytic anemia is of paramount importance. Laboratory parameters of microangiopathic hemolytic anemia i.e. schitocytosis and increased LDH and indirect hyperbilirubinemia support the diagnosis. Plasma exchange is the treatment of choice. Post stem cell transplant TTP carries a poorer prognosis.Introduction:Thrombotic thrombocytopenic purpura (TTP) is a disorder characterized by microangiopathic hemolytic anemia and thrombocytopenia associated with fever, renal dysfunction and neurological manifestations. Without treatment, TTP is almost uniformly fatal with a mortality rate approaching 90%. With the timely institution of therapeutic plasma exchange mortality decreases to about less than 10% (1). Recent reports indicate that rituximab can induce remission in the majority of patients with classic TTP (2). We report here 13 cases of TTP who were treated at our hospital in last 4 years. Six of these patients developed features of TTP post allogenic stem cell transplantation.Materials and Methods: The study included retrospective analysis of patients who presented with the features of TTP. Patients with characteristic features of TTP included two or more features among the pentad commonly considered diagnostic of TTP. Evidence of microangiopathic hemolytic anemia and thrombocytopenia were the minimal requirement for the diagnosis with or without fever, renal dysfunction and neurological manifestations. Coagulation profile included prothrombin time and APTT. Liver and kidney function analysis was done in all patients. Response was assessed by clinical and laboratory parameters with monitoring platelet counts, LDH, and schistocytes in the peripheral blood film. Patients with LDH in normal range and platelet counts more than 100,000/µl were considered to have achieved remission.Results: Patients with classic TTP recovered with plasma exchange and/or rituximab. Post-transplant TTP patients had a poorer prognosis as five out of six post-transplant TTP patients died.Discussion: TTP can have a varied clinical presentation and can be associated with many other diseases. Our case series highlight the varied manifestations and associations of TTP and their management and outcome. TTP is a medical emergency and needs high index of suspicion for the diagnosis. In our series, TTP was diagnosed by the findings of thrombocytopenia and hemolytic anemia evidenced by presence of schistocytes in the peripheral blood film and increased LDH, in the absence of coagulopathy. TTP should be suspected in the presence of microangiopathic hemolytic anemia and thrombocytopenia (1,3), and treatment should be started immediately, as delay in treatment can increase the mortality (1). Plasma exchange has changed the prognosis of this highly fatal disease to a highly curable disease. Rituximab has further improved the management of TTP (2). Patients with classic TTP were treated with plasma exchange but 3 patients also required rituximab. All patients with classic TTP are in remission.Transplant-associated microangiopathy (TAM) is a MAHA and thrombocytopenia that occurs after bone marrow transplantation. Patients with post-transplant TTP were diagnosed based on thrombocytopenia and features of microangiopathic hemolytic anemia with schistocytosis and raised LDH, in the absence of coagulopathy. They were treated with FFP and steroids, as plasma exchange is not beneficial for post-transplant TTP (1). Repeated plasma exchange with increased frequency and/or rituximab therapy are the agents of choice in relapsing disease (3). Rituximab is a safe and effective treatment for newly diagnosed TTP, and has been shown to decrease the number of plasma exchange required to achieve remission. We used rituximab in 3 patients and all improved. Post transplant MAHA carried poor prognosis.Conclusion: Diagnosis of TTP requires a high index of suspicion and prompt treatment with plasma exchange, which results in a high cure rate. Rituximab is useful in patients relapsing or showing partial recovery. Plasma exchange has not been reported to be effective in post-transplant TTP.Acknowledgment: We are thankful to Ms Bharti Sharma for compiling the data. DisclosuresNo relevant conflicts of interest to declare.

Thrombotic microangiopathy in a very young infant with mitral valvuloplasty

Thrombotic microangiopathies (TMA) are microvascular occlusive disorders characterized by systemic or intrarenal platelet aggregation, thrombocytopenia, and red cell fragmentation. Post-operative TMA mostly occurs in adult patients with cardiovascular surgery, with the distinct pathophysiology from classical thrombotic thrombocytopenic purpura (TTP) although the exact pathophysiology remains unclear. A one-month-old infant developed TMA after the initial surgery of double outlet right ventricle. ADAM metallopeptidase with thrombospondin type 1 motif 13 (ADAMTS13) activity was sustained (64%) with the undetectable inhibitor. Von Willebrand factor (VWF) multimer analyses showed absent high-molecular weight multimers. Echocardiography disclosed severe mitral regurgitation. The mitral valve repair 32 days after the initial valvuloplasty led to prompt resolution of TMA. These suggested that TMA occurred in association with valvulopathy-triggered turbulent shear flow, mechanical hemolysis and endothelial damage. The consumption of large VWF multimers might account for the vascular high shear stress shown in Heyde syndrome. The youngest case of post-operative TMA underscores the critical coagulopathy after the first surgical intervention for congenital heart disease.

Hiperpigmentación cutánea en el déficit de vitamina B12

Thrombotic microangiopathies (TMAs) are a group of life-threatening conditions requiring urgent management and characterized by a clinical triad of microangiopathic hemolytic anemia, thrombocytopenia, and ischemic tissue injury. Severe vitamin B12 (Cobalamin—Cbl) deficiency or defective cobalamin metabolism, particularly defects in intracellular B12 metabolism, may lead to a TMA-like picture. The latter has been termed metabolism-mediated TMA (MM-TMA). This confusing picture is mediated partly by ineffective erythropoiesis with significant red cell fragmentation resulting in a hemolytic pattern, coupled with reduced platelet production and endothelial injury with organ damage resulting from accumulated toxic byproducts of B12 dysmetabolism. However, unlike in classic thrombotic thrombocytopenic purpura, where therapeutic plasma exchange has to be initiated promptly, cases of MM-TMA can be treated, if diagnosed properly, with adequate B12 replacement.

Atypical presentations of thrombotic thrombocytopenic purpura: a diagnostic role for ADAMTS13.

Thrombotic thrombocytopenic purpura (TTP) is an acute, life threatening disease. Only a minority of patients expresses the complete clinical presentation and unusual manifestations can occur. Demonstration of low activity levels of ADAMTS13 (<5%) is highly specific for the diagnosis of TTP. This study reports a series of five cases of TTP presenting with a thrombotic event and no hematological findings. Detailed chart reviews on these patients were conducted. We identified two patients whose first attack of TTP presented as a thrombotic episode without microangiopathic hemolytic anemia and thrombocytopenia, only to be diagnosed as TTP days later, after the appearance of hematological signs. We also describe three cases of classical TTP relapsing atypically as cerebrovascular accidents without hematological signs. Low levels of ADAMTS13 activity were detected and facilitated the diagnosis. The neurological manifestations disappeared concurrent with normalization of ADAMTS13 activity level after plasma exchange. This study underscores the importance of having a high clinical suspicion of TTP in cases of thrombosis even without hematological abnormalities in patients with previous attacks of TTP. In this clinical scenario, measurement of ADAMTS13 activity is important for diagnosis and early administration of treatment.

Postoperative thrombotic thrombocytopenic purpura

Thrombotic thrombocytopenic purpura (TTP) is a rare, life-threatening disease characterized by acute episodes of thrombocytopenia and microangiopathic hemolytic anemia occurring due to platelet and von Willebrand factor deposition and hyaline thrombi formation in arterioles and capillaries throughout the body, which results in organ ischemia. TTP can be idiopathic or secondary, and there are several causes of secondary TTP. There is a clinical syndrome resembling TTP that occurs after surgical procedures, so-called "postoperative TTP" (pTTP). In this review, the differential diagnosis, pathogenesis and clinical and laboratory features of pTTP, together with the treatment modalities and outcomes of the patients, are discussed. The pTTP is a diagnosis of exclusion, and disseminated intravascular coagulation, heparin-induced thrombocytopenia and medication-induced effects should be ruled out. As in classical TTP, patients with pTTP should be diagnosed and treated with therapeutic plasma exchange (TPE) as early as possible to reduce their morbidity and mortality. Although rarely seen, surgeons and physicians of all specialties should be alert to the possibility of pTTP, and since pTTP is a life-threatening event that usually can be treated successfully with TPE, especially when diagnosed early in its course, it is critical to recognize and treat pTTP promptly.

Ticlopidine‐associated ADAMTS13 activity deficient thrombotic thrombocytopenic purpura in 22 persons in Japan: a report from the Southern Network on Adverse Reactions (SONAR)

Ticlopidine‐associated <scp>ADAMTS</scp>13 activity deficient thrombotic thrombocytopenic purpura in 22 persons in Japan: a report from the Southern Network on Adverse Reactions (<scp>SONAR</scp>)

The Alternate Complement Pathway in Thrombotic Thrombocytopenic Purpura

AbstractAbstract 3342The thrombotic microangiopathies (TMA) thrombotic thrombocytopenic purpura (TTP) and atypical hemolytic uremic syndrome (aHUS) involve progressive microvascular thrombi, endothelial cell (EC) injury, vascular ischemia, and severe end-organ damage. Acquired TTP is often associated with autoantibody-mediated suppression of the ADAMTS13 vWF cleaving protease, causing vWF multimer accumulation and platelet aggregation. aHUS is associated with dysregulation of the alternate complement pathway through mutation in and/or autoantibodies against, complement regulatory proteins. It is responsive to the anti-C5 mAb eculizumab. TTP, by contrast, usually responds to plasma exchange, but in the refractory setting there are few effective treatments. We hypothesized that dysregulation of the alternate complement pathway represents a susceptibility factor for EC injury in at least a subset of TTP patients. Our objective was to identify the degree of complement dysregulation in acute TTP vs. other TMAs in vivo, and correlate these data with (1) the ability of plasma from acute TTP and aHUS patients to induce apoptotic injury in primary human microvascular EC in vitro and (2) the potential of eculizumab to block this injury.Plasmas from acute TMA patients (TTP n=12, malignancy-associated aHUS n=6, ticlopidine-associated TTP n=4, systemic Degos disease n=1), and healthy controls (n=4) were collected at time of presentation. Samples were assayed for terminal complement components sC5b-9 (MAC, membrane attack complex) and C5a by ELISA. Genomic DNA was isolated from these plasmas and amplified by standard DNA PCR, followed by semi-nested PCR using primers designed around the exon sequences of complement factor H (CFH), complement factor I (CFI) and MCP (CD46) known to be mutated in 60–80% of aHUS cases. Amplicons were sequenced and correlated with a database of previously reported mutations and SNPs with varying degrees of functional significance in the complement regulatory pathway. In our in vitro model for plasma-mediated EC injury, primary human dermal microvascular ECs were starved in medium lacking EC growth factors and then incubated for 18–24 hours with 1–2% plasma (v/v) in the presence or absence of pharmacologic levels of anti-C5 mAb (100–250μg/ml). Apoptosis was assessed by ELISA-based quantification of cytoplasmic histone-associated DNA fragments from cell lysate and propidium iodide labeling with construction of DNA histograms and assessment of A0 peaks by flow cytometry.We found significantly elevated plasma levels of C5a in all subsets of patients with TMAs compared to control plasma (42.8 ng/ml +/− 6.2 vs. 32 ng/ml +/− 6.8; p=0.014). We also found markedly elevated levels sC5b-9 in these TMAs compared to controls (1852.0 ng/ml +/− 1169.8 vs 598.8 +/− 338.7; p=0.012). Little variation was seen in TTP vs. aHUS and other TMAs, regardless of ADAMTS13 status. Complement mutations in CFH and CFI were identified in 14 (66.7%) of TMA patients: 41.6% TTP, 60% malignancy-aHUS, 100% ticlopidine TTP. In terms of interference with TMA plasma-induced MVEC apoptosis in vitro, EC injury was blocked by anti-C5 mAb eculizumab in 8 of 19 cases (5 TTP, 2 aHUS, 1 Degos). Correlation of sensitivity to plasma-mediated EC apoptosis and blockade with eculizumab with levels of terminal complement components, presence of complement regulatory factor mutations, levels of ADAMTS13 activity, and anti-ADAMTS13 antibody titers are underway.We conclude that dysregulation of the alternate complement pathway may represent a susceptibility factor in the pathophysiology of many TMAs, not only aHUS. Blockade of C5 may offer a therapeutic avenue for some patients with refractory TTP. Indeed, in a recent report our group noted the rescue of a patient with classic TTP, including ADAMTS13 activity <5% and anti-ADAMTS13 IgG, refractory to plasma exchange and a variety of immune suppressive regimens, utilizing eculizumab (Chapin J, et al. Brit J Hematol, 2012). Defining this subset, and the potential for clinical response to anti-C5 therapy, will involve exploration of other complement and complement regulatory factor mutations and autoantibodies. Disclosures:Off Label Use: Eculizumab is not FDA approved for use in the treatment of TTP. Laurence:Alexion Pharmaceuticals: Consultancy, Speakers Bureau.

Breast Cancer-Associated Thrombotic Microangiopathy

Background: Thrombotic microangiopathy (TMA) is defined as thrombocytopenia and microangiopathic hemolytic anemia. Cancer-associated TMA, a rare but fatal condition, seems an entity distinct from classical thrombotic thrombocytopenic purpura (TTP)/hemolytic uremic syndrome (HUS). Patients and Methods: All patients with breast cancer-associated TMA treated at our institution between 2003 and 2008 were analyzed retrospectively. To elucidate pathophysiological mechanisms, we measured the serum activity of the metalloprotease ADAMTS13. Results: 8 patients were identified. All showed bone marrow infiltration of breast cancer as well as thrombocytopenia, schistocytes, and hemolytic anemia. ADAMTS13 activity was mildly decreased in 4/6 patients (20–108%, normal range 30–120%), but none showed severely low levels as is characteristic of classical TTP. 6 patients were treated with anthracycline-containing fractionated chemotherapy, 5/6 patients experienced partial response. Overall survival was 13 months. Fractionated chemotherapy was well tolerated. Conclusions: Cancer-associated TMA has an underlying mechanism different from classical TTP. While bone marrow infiltration might be of major relevance, ADAMTS13 deficiency seems to be an epiphenomenon. Fractionated chemotherapy resulted in higher remission rates and comparatively long survival.

Use of Anti-C5 Monoclonal Antibody Eculizumab in the Treatment of a Patient with Refractory Idiopathic Thrombotic Thrombocytopenic Purpura (TTP)

Abstract 4666 Background:Case reports and two prospective, controlled trials document the efficacy of anti-C5 monoclonal antibody eculizumab in the treatment of refractory atypical hemolytic uremic syndrome (aHUS) as well as in aHUS patients requiring chronic plasma exchange. It has shown efficacy in the presence and absence of defects in complement (C) and C regulatory proteins. However, eculizumab has not been previously used in TTP associated with low ADAMTS13 activity, despite the many shared clinical and pathologic features of TTP with aHUS. Case report:A 27 y.o. white male with a history of inflammatory bowel disease presented with fever, thrombocytopenia, and microangiopathic hemolytic anemia, and rapidly developed renal failure, seizures, and coma. ADAMTS13 activity was <5% of normal (IgG anti-ADAMTS13 inhibitor titer of 160), and LDH, 476 on presentation, steadily rose to 1321 by day 8 (Figure). Daily plasma exchange, initiated on hospital day 1, produced no improvement in platelet count, LDH, creatinine, schistocyte levels on peripheral blood smear, mental status, or seizure activity through day 8. Admission stress dose steroids were then increased to 60mg/day prednisone, and vincristine, N-acetylcysteine, and weekly rituximab infusions were initiated, with no change in clinical or laboratory status (Figure). Skin biopsies on day 21 revealed intense granular deposits of C3d, C4d, and the terminal membrane attack complex C5b-9 within and around vessels, including endothelium and pericytes, suggesting a role for local vascular C activation. Hence, eculizumab (900mg IV once a week for 4 weeks, with two supplemental weekly doses of 600mg to adjust for some loss of antibody with plasma exchange, and a final 1200mg dose) was added to the treatment regimen. Platelets increased to 71 and LDH declined to 293 by day 31, and ADAMTS13 activity normalized by day 54 (85%). Plasma exchange and eculizumab were discontinued, and a steroid taper initiated on day 56 when the platelet count was 213K, LDH 145, and creatinine 1.07. The beginning of a rapid decent in platelet count was noted on day 85, accompanied by a decrease in ADAMTS13 activity to 9%. Eculizumab alone (900mg) was restarted. Platelet count, Hb, and creatinine returned to normal within 9 days. Relevant clinical data:Figure and C1q and complement regulatory proteins: factors H, I, and B: normal. Outcome:In remission four months after initial presentation, receiving biweekly eculizumab infusions as an outpatient. Conclusion:Eculizumab was associated with remission induction in a patient with classic idiopathic TTP refractory to plasma exchange. Although multiple, overlapping initial therapies obfuscate assignment of efficacy to a single agent during initial treatment, remission obtained with eculizumab alone on relapse suggests its efficacy. Eculizumab should be considered in patients with refractory TTP. Eculizumab treatment is ongoing in this patient, but the duration of the treatment period remains to be elucidated. Our study also emphasizes that vascular C activation, possibly triggered by endothelial cell injury, may be a critical factor in at least some cases of TTP. C5b-9 induces a secretory response in endothelium to elaborate ultra high molecular weight von Willebrand factor multimers which would be ineffectually cleaved in patients with antibodies to ADAMTS13. This could lead to a dysregulated thrombotic microangiopathy. Blocking C5 formation may thus address a critical upstream pathway relevant to TTP as well as aHUS. Disclosures:Off Label Use:Eculizumab treatment of TTP is an off-label use. [Display omitted]

Thrombotic Microangiopathy in Haematopoietic Stem Cell Transplantation

Each year in the US, more than 10 000 patients benefit from allogeneic haematopoietic stem cell transplantation (HSCT), a modality that offers an excellent chance of eradicating malignancy but confers a higher risk of treatment-related mortality. An uncommon but devastating consequence of HSCT is transplantation-associated thrombotic microangiopathy (TA-TMA). The incidence of TA-TMA ranges from 0.5% to 76%, with a mortality rate of 60-90% despite treatment. Although there appears to be a consistent treatment approach to idiopathic thrombotic thrombocytopenic purpura (TTP) using plasma exchange, corticosteroids and rituximab, the treatment strategies for TA-TMA are perplexing, in part, because the literature regarding this complex condition does not provide true consensus for incidence, aetiology, diagnostic criteria, classification and optimal therapy. The classic definition of idiopathic TTP includes schistocytes on the peripheral blood smear, thrombocytopenia and increased serum lactate dehydrogenase. Classic idiopathic TTP has been attributed to deficient activity of the metalloproteinase responsible for cleaving ultra-large von Willebrand factor multimers. This protease is a member of the 'a disintegrin and metalloprotease with thrombospondin type 1 motif' family and is subsequently named ADAMTS-13. Severely deficient ADAMTS-13 activity (<5% of normal) is associated with idiopathic TTP in 33-100% of patients. In constrast to the pathophysiology of idiopathic TTP, patients with TA-TMA have >5% ADAMTS-13 serum activity. These data may explain why plasma exchange, a standard treatment modality for idiopathic TTP that restores ADAMTS-13 activity, is not effective in TA-TMA. TA-TMA has a multifactorial aetiology of endothelial damage induced by intensive conditioning therapy, irradiation, immunosuppressants, infection and graft-versus-host disease. Treatment consists of substituting calcineurin inhibitors with an alternative immunosuppressive agent that possesses another mode of action. One candidate may be daclizumab, especially in those with mild to moderate TMA. Rituximab therapy or the addition of defibrotide may also be beneficial. In general, plasma exchange is not recommended.

Acute postoperative thrombotic thrombocytopenic purpura following hysterectomy and lymphadenectomy for endometrial cancer

Background Thrombotic thrombocytopenic purpura (TTP) in the acute postoperative setting is a recently recognized syndrome that, similar to classic or idiopathic TTP, presents variably with microangiopathic hemolytic anemia, thrombocytopenia, fever, renal failure, and mental status changes. Though most reports of postoperative TTP are in conjunction with cardiac or vascular surgery, it has also been reported following orthopedic and abdominal surgeries. Case We present a case of a 53 year-old female diagnosed with metastatic poorly differentiated endometrial cancer who developed TTP the day following her cytoreductive cancer surgery. Conclusion To our knowledge, this represents the first reported case of postoperative TTP following gynecologic cancer surgery. Because the presentation can be confused with other early postoperative complications, awareness of this syndrome is essential as initiation of plasmapheresis can be life-saving.

Prospective study on the behaviour of the metalloprotease ADAMTS13 and of von Willebrand factor after bone marrow transplantation

Thrombotic microangiopathies (TMAs) are rare but serious complications of bone marrow transplantation (BMT). Clinical manifestations are similar to those of thrombotic thrombocytopenic purpura (TTP), but prognosis is generally poorer despite plasma exchange. The enzymatic activity of the plasma metalloprotease ADAMTS13, which cleaves ultralarge thrombogenic multimers of von Willebrand factor (VWF) derived from activated endothelial cells, is very low or undetectable in patients with classic TTP, and protease deficiency is thought to play a mechanistic role in the formation of platelet thrombi in the microcirculation. This is the first prospective study to evaluate the incidence of TMA in 46 consecutively recruited patients undergoing autologous or allogeneic BMT and explore in parallel the behaviour of ADAMTS13, VWF antigen and VWF multimer size. The incidence of post-BMT TMA was 6% (three of 46); all cases occurred after allogeneic BMT. Compared with baseline values plasma ADAMTS13 activity was significantly reduced in patients undergoing BMT, particularly after the conditioning regimen (mean values: 50 +/- 22 vs. 77 +/- 32%; P < 0.0001). In the three patients who developed TMA, ADAMTS13 decreased after conditioning, but was very low in one case only (8%). VWF antigen levels progressively increased after the conditioning regimen (228 +/- 75 vs. 178 +/- 76% at baseline, P = 0.002). The mean proportion of high-molecular weight VWF multimers did not change in the various stages of BMT, even though ultralarge multimers were transiently found in same cases with and without TMA. Hence, the measurements evaluated in this study are not clinically useful to predict the occurrence of post-BMT TMA.

Deficient activity of von Willebrand factor-cleaving protease in thrombotic thrombocytopenic purpura in the setting of adult-onset Still's disease

Deficient activity of von Willebrand factor-cleaving protease in thrombotic thrombocytopenic purpura in the setting of adult-onset Still's disease

Post-operative thrombotic thrombocytopenic purpura: a review.

Post-operative thrombotic thrombocytopenic purpura (TTP) is a recently recognised life-threatening clinical syndrome with considerable similarity to classic TTP in presentation and response to early treatment with plasma exchange. To date, 29 cases of TTP associated with surgery have been reported. The majority of cases have complicated vascular surgeries, with a few cases seen following gastrointestinal or orthopaedic procedures. Characteristically, patients develop microangiopathic haemolytic anaemia and consumptive thrombocytopenia 5 to 9 days following surgery with variable presence of fever, impaired renal function and altered mental status. The pathogenesis of post-operative TTP is speculative but may involve the release of large amounts of high-molecular-weight von Willebrand factor (vWF) multimers due to endothelial damage resulting from surgery in the setting of marginal levels of vWF-cleaving enzyme. The myriad of common post-surgical complications that may present with clinical manifestations similar to TTP may result in confusion with the potential for delay in the initiation of life-saving plasma-exchange therapy. It is important that physicians be alert to the phenomenon of post-operative TTP so that prompt recognition and treatment will prevent serious morbidity or mortality.

Severe ADAMTS-13 deficiency in childhood

Thrombotic thrombocytopenic purpura (TTP) is a rare microangiopathic disorder with high morbidity and significant mortality. The primary form of TTP is caused by severe deficiency, acquired or hereditary, of the von Willebrand factor cleaving protease (VWF-CP), ADAMTS-13. Because TTP occurs less frequently in children, general pediatricians are not well informed about the spectrum of clinical symptoms and altered laboratory values, increasing the risk of nondiagnosis and possible fatal outcome. If renal involvement is present, the condition can easily be misdiagnosed as hemolytic-uremic syndrome (HUS). We present a case series of children with severe VWF-CP deficiency with emphasis on the clinical heterogeneity responsible for misdiagnosis and inappropriate treatment. The inherited form may involve onset of symptoms ranging from isolated thrombocytopenia to the full clinical picture characteristic of classical TTP. The most common assumed diagnoses of oligosymptomatic forms are immune thrombocytopenia (ITP) and Evans syndrome, respectively. Accordingly, this article is directed towards pediatricians on neonatal and intensive care units, as well as their colleagues specializing in nephrology, hematology, and neurology.

The von Willebrand Factor-Cleaving Protease (ADAMTS-13) and the Diagnosis of Thrombotic Thrombocytopenic Purpura (TTP)

Thrombotic thrombocytopenic purpura (TTP) is a life threatening disorder characterized by microangiopathic hemolytic anemia and thrombocytopenia as a result of microvascular platelet clumping often accompanied by ischemic organ dysfunctions such as neurological abnormalities or renal insufficiency, and fever. Until the sixties of the 20th century TTP remained an almost universally fatal disorder. The introduction of plasma exchange therapy (PE) with replacement of fresh frozen plasma has dramatically improved the survival of patients with acute TTP from less than 10% to about 80-90% and is now considered the therapy of choice. Severe deficiency of the von Willebrand factor (VWF)-cleaving protease, now denoted as ADAMTS-13, prevents normal processing of unusually large VWF multimers released from endothelial cells and it is assumed that their persistence is responsible for the formation of platelet thrombi in the microvasculature, a pathophysiological hallmark of acute TTP. An ADAMTS-13 activity of <5% of the normal is a specific finding for acute classical TTP. However, the sensitivity of this finding for the clinical diagnosis of TTP is equivocal with reported prevalences ranging from 33 -100%. Today, two forms of classical TTP are distinguished. Hereditary TTP, also known as Upshaw-Schulman syndrome, is caused by severe constitutionalADAMTS-13 deficiency due to compound heterozygous or homozygous mutations of theADAMTS13 gene and patients often present with a chronic relapsing course. The acquired or sporadic form of TTP is caused by circulating autoantibodies inhibiting ADAMTS-13 activity. Relapses are also frequent in acquired TTP occurring in about 35-50% of survivors of a first bout. Despite improved treatment modalities, patients suffering from acute bouts of TTP constitute a challenge for any clinician as mortality and morbidity rates are still considerably high.