Familial Thrombotic Thrombocytopenic Purpura Research Articles

Report of two unrelated cases of Familial Thrombotic Thrombocytopeic Purpura

Thrombotic Thrombocytopenic Purpura (TTP) is a rare microangiopathic disorder characterised by the pentad of microangiopathic hemolytic anemia, thrombocytopenic purpura, neurologic abnormalities, fever, and renal disease. Decreased production and/or activity of ADAMTS13 is the cause of this disorder. ADAMTS13 is a metalloproteinase which is responsible of the cleavage of high weight multimers of von Wilebrand factor. Its acquired form is usually seen in adults and is due to antibody formation against the enzyme. But even rarer familial and relapsing forms (Upshow-Scholman syndrome) are due to enzyme underproduction and can be seen in pediatric age group. Here, the authors reported two unrelated cases of familial TTP from Guilan province in the north of Iran.

Analysis of clinical and laboratory characteristics in 42 patients with thrombotic thrombocytopenic purpura from a single center in China

Thrombotic thrombocytopenic purpura (TTP) is a life-threatening disease characterized by microvascular platelet deposition and thrombus formation with resulting microangiopathic hemolytic anemia. Deficiency of the von Willebrand factor cleavage protease, also known as ADAMTS 13, has been implicated as an important etiological factor in TTP. Little studies were obtained on Chinese patients with TTP until now. Our aim was to analyze the clinical features, outcome and laboratory characteristics of Chinese TTP patients, and determine whether plasma ADAMTS 13 activity is decreased in TTP and its diagnostic value for TTP. Forty-two TTP patients (29 females; 13 males) admitted to our hospital from 1998 to 2010 were analyzed. There were 34 patients (81%) with the triad of TTP, including hemolytic anemia, thrombocytopenia and neurologic abnormalities; 7 (16.7%) had the classical pentad of TTP. Major etiologic factors were acquired autoimmunological abnormalities (31%); no familial TTP was identified in this series. The schistocytes of peripheral blood smears were present in all cases with a mean frequency of 4.6% (range from 0.3% to 13.4%). Plasma ADAMTS 13 activity was determined in 22 patients with the FRET-vWF86 assay. Only 4 idiopathic TTP patients (18.2%) had severe ADAMTS 13 deficiency (activity<10%); 9 (40.9%) had moderate decrease of ADAMTS 13 activity (activity: 10-40%); another 9 (40.91%) had normal ADAMTS 13 activity (>40%). T lymphocyte subpopulation was measured in 23 TTP patients with FACS Calibur; 14 of the 23 (60.9%) had significantly decreased CD4 cells count and CD4/CD8 ratio, suggesting cellular immune dysfunction may be involved in the pathogenesis of TTP. In the studies, plasmapheresis is the main therapeutic method. 26 of 31 patients (83.9%) accepting plasmapheresis achieved complete remission; those patients who only underwent plasma infusion had low remission rate (18.2%) and high mortality (9/11; 81.8%). Four patients with packed RBC infusion manifested transient exacerbation of neurologic or psychiatric symptoms. In conclusion, the diagnosis of TTP in China is still based on clinical features including evidence of microangiopathic hemolysis. Severe ADAMTS 13 activity deficiency might be a valuable indicator for idiopathic TTP diagnosis. Further studies are needed to determine the real value of ADAMTS 13 activity for TTP diagnosis and whether T lymphocytes subset dysregulation plays important role in TTP pathogenesis.

Complement activation in thrombotic microangiopathies

Complement activation in thrombotic microangiopathies

Rituximab Has Similar Efficacy in Treatment of Acute Refractory or Chronic Relapsing Idiopathic Thrombotic Thrombocytopenic Purpura (TTP) and Refractory Secondary TTP: A Systematic Review

Abstract 4673 Background:Thrombotic thrombocytopenic purpura (TTP) is a potentially life-threatening disorder. Secondary TTP was known to be more resistant to plasma exchange and have higher mortality. Limited clinical data suggest that rituximab may be effective in the treatment of acute refractory or chronic relapsing nonfamilial idiopathic TTP (ITTP) as well as refractory secondary TTP (STTP). We performed a systematic review to evaluate the comparative efficacy of rituximab in ITTP and STTP. Method:An electronic literature search of Medline, CINAHL and the Cochrane library databases using the terms “rituximab” and “thrombotic” yielded 179 articles from March 2002 to June 2011. Studies were included if they met the following criteria: TTP in a first episode or subsequent relapse and TTP refractory to plasma exchange. Exclusion criteria were prophylactic administration of rituximab to patients in remission and familial TTP. Secondary TTP cases were author-defined. Case series without extractable individual data were excluded. Two-Tailed Fisher Exact Test was used to investigate the difference in complete remission rates between ITTP and STTP. Independent-Samples Mann-Whitney U Test was applied to detect the difference in platelet recovery days. Result:20 case series and 33 case reports including a small prospective study were eligible. Individual data of 139 patients from Europe, Asia, Australia, South and North America were analyzed. Overall, median age was 40 years (range: 1–72). Male constituted 30% and female 70%. Complete remission rate was 88% (90 out of 102) and 84% (31 out of 37) for ITTP and STTP respectively. There was no statistically significant difference in complete remission rates between the two groups (Two-Tailed Fisher Exact Test p value = 0.569). Median follow-up time was 12 months. Median platelet recovery (more than 150×109/L) from the first dose of rituximab was 8 days (range: 2–74) and 19 days (range: 7–90) for ITTP and STTP respectively. The distribution of platelet recovery days was the same between ITTP and STTP (Independent-Samples Mann-Whitney U Test p value = 0.132). Conclusion:Rituximab has the same efficacy in both STTP and ITTP in terms of response rate and platelet recovery days. It appears to be effective and well-tolerated. We recommend the use of rituximab as a salvage therapeutic modality in refractory acute or chronic relapsing nonfamilial idiopathic as well as secondary TTP. Disclosures:No relevant conflicts of interest to declare.

ADAMTS-13 gene expression in antiphospholipid syndrome.

Antiphospholipid syndrome (APS) is an autoimmune disorder characterized by recurrent thrombosis and fetal mortality. Thrombotic microangiopathy (TMA) is an important histological finding in catastrophic APS (CAPS) and in APS patients with nephropathy. Analysis of familial thrombotic thrombocytopenic purpura patients showed that there are mutations in the ADAMTS-13 gene that lead to functional defects in the ADAMTS-13 enzyme. The aim of this study was to investigate the prevalence of the aforementioned mutations in APS, as well as to evaluate the level and activity of the ADAMTS-13 enzyme in patients with APS. C365del, Q449stop codon, P475S, and C508Y mutations were analyzed in APS patients. Transcriptions were analyzed using real-time PCR, and the level and activity of ADAMTS-13 were analyzed via fluorogenic assay. None of the mutations tested were present in the patient or control groups. The level of ADAMTS-13 mRNA in the patient group was 50% lower than that in the control group. Although a significant difference in ADAMTS-13 activity was not observed between the patient and control groups, a significant association was observed with the level of ADAMTS-13 (p<0.0001). The level and activity of ADAMTS-13 were not associated with thrombotic complications, thrombocytopenia, or pregnancy complications in the patients with APS.

The Role of Endothelial Cell Injury in Thrombotic Microangiopathy

Thrombotic microangiopathy (TMA) refers to a clinical and pathologic syndrome in which endothelial injury results in the manifestations of thrombocytopenia, microangiopathic hemolytic anemia, and kidney injury. A host of causes may induce endothelial injury and TMA, including enteric bacterial toxins, deficiency or dysfunction of complement regulatory proteins, deficiency or inhibition of von Willebrand factor-cleaving proteases, and factors that inhibit endothelial cell proliferation and turnover. This has led specialists to concentrate on these specific inciting factors in terms of designing treatment and management. However, a key and less recognized factor is the underlying level of endothelial health. Many persons with hereditary causes may remain disease free for years or may never develop disease. Others with acute inciting events, such as Escherichia coli O157 enteritis, never manifest TMA. Experimental studies document the importance of specific factors, such as endothelial nitric oxide levels, in helping protect animals from TMA. This suggests that one might approach the management of TMA not simply with specific treatments aimed at the underlying hereditary cause or inciting event, but rather at general measures that may improve overall endothelial health. We propose studies to determine whether interventions that improve endothelial health, such as the administration of angiotensin-converting enzyme inhibitors, statins, vitamin C, allopurinol, or nitric oxide-producing drugs, may be able to prevent TMA, even in persons with underlying hereditary conditions that otherwise would predispose them to these diseases.

Clinical study on five cases of thrombotic thrombocytopenic purpura complicating pregnancy

The aim of this study was to investigate the potential role of ADAMTS13 analysis in the early recognition and management of thrombotic thrombocytopenic purpura (TTP) in pregnant women. Five cases of TTP were evaluated retrospectively. Clinical and laboratory findings, von Willebrand factor (vWF)-cleaving metalloprotease (ADAMTS13) activity and maternal and neonatal outcome were recorded and analysed. Five cases were all nulliparous. ADAMTS13 assay was performed and the enzyme activity was less than 5% of the normal controls in three cases. Gene mutation in the 9th exon resulting in amino acid exchange 349Arg→Cys in ADAMTS13 was identified in one patient. After treatment including transfusion of fresh-frozen plasma (n = 5), packed red blood cells (n = 5), platelet transfusions (n = 2) and/or continued renal replacement therapy (CRRT) (n = 1) and plasma exchange (n = 2), three patients were alive, one died on postpartum day 6 in hospital without plasma exchange and one of familial TTP died three months after discharge. With increasing awareness, extra-attention must be paid to patients with thrombotic microangiopathy and to measurement of ADAMTS13 activity for early diagnosis. Although severe ADAMTS13 deficiency may be helpful for TTP, it may not be sensitive enough to identify all TTP patients. Therefore, despite ADAMTS13 result positive or negative, prompt aggressive management should include early termination of pregnancy, plasma transfusion and/or plasma exchange.

Moderate to severe thrombocytopenia during pregnancy

Objective The objective was to investigate obstetric risk factors, complications, and outcomes of pregnancies complicated by moderate to severe thrombocytopenia. Materials and methods A retrospective case-control study comparing 199 pregnant women with moderate to severe thrombocytopenia (platelet count below 100 × 10 9/l) with 201 pregnant women without thrombocytopenia, who delivered between January 2003 to April 2004. Stratified analysis, using the Mantel–Haenszel procedure was performed in order to control for confounders. Results The main causes of thrombocytopenia were gestational thrombocytopenia (GT) (59.3%), immune thrombocytopenic purpura (ITP) (11.05%), preeclampsia (10.05%), and HELLP (Hemolysis, elevated liver enzymes and low platelet count) syndrome (12.06%). Women with thrombocytopenia were significantly older (30.7 ± 5.9 versus 28.7 ± 5.7; p = 0.001) compared with patients without thrombocytopenia, and had higher rates of labor induction (OR = 4.0, 95% CI = 2.2–7.6, p < 0.001) and preterm deliveries (OR = 3.5, 95% CI = 1.9–6.5, p < 0.001). Even after controlling for labor induction, using the Mantel–Haenszel technique, thrombocytopenia was significantly associated with preterm delivery (weighted OR = 3.14, 95% CI = 1.7–6.0, p < 0.001). Higher rates of placental abruption were found in pregnant women with thrombocytopenia (OR = 6.2, 95% CI = 1.7–33.2, p = 0.001). In a comparison of perinatal outcomes, higher rates of Apgar scores <7 at 5 min were noted in infants of mothers with thrombocytopenia (OR = 6.3, 95% CI = 1.8–33.8, p = 0.001), intrauterine growth restriction (IUGR; OR = 4.6, 95% CI = 1.5–19.1, p = 0.003), and stillbirth (65/1000 versus 0 p < 0.001). These adverse perinatal outcomes were found in rare causes of thrombocytopenia such as disseminated intravascular coagulation (DIC), familial thrombotic thrombocytopenic purpura (TTP), anti-phospholipid antibodies (APLA) syndrome, and myeloproliferative disease, and not among patients with GT. Conclusions Moderate to severe maternal thrombocytopenia points to a higher degree of severity of the primary disease, which increases perinatal complications. However, the adverse outcome is specifically attributed to preeclampsia, HELLP syndrome, and rare causes, while the perinatal outcome of GT and ITP is basically favorable. Special attention should be given to patients with thrombocytopenia due to preeclampsia, HELLP syndrome, and rarer causes during pregnancy.

Familial Thrombotic Thrombocytopenic Purpura in Three Siblings.

Thrombotic thrombocytopenic purpura (TTP) is characterized by microangiopathic hemolytic anemia, systemic platelet aggregation, organ ischemia, thrombocytopenia, and fragmentation of erythrocytes. The disease is caused either by congenital deficiency of von Willebrand factor-cleaving protease (ADAMTS 13) or due to acquired autoantibodies against ADAMTS 13. We have been treating three siblings with recurrent episodes of hemolytic anemia, thrombocytopenia, neurological and renal dysfunctions during last 10 years. The oldest brother presented with thromboangiopathic anemia, thrombocytopenia (platelets account below 30x103/μl), episode of unconsciousness, proteinuria and splenomegaly at the age of 15 years. Splenectomy was done with the improvement in thrombocytopenic purpura. But he has suffered from permanent microangiopathic hemolytic anemia, and developed renal insufficiency. He died due to intestinal bleeding last year. Two younger siblings, a 12 year old girl and an 11 year old boy also presented with recurrent symptoms of microangipathic hemolytic anemia and thrombopcytopenia with or without renal dysfunction since early childhood. The diagnosis of congenital TTP in this family was based on clinical symptoms and tests of ADAMTS 13 and its inhibitor. The activity of ADAMTS 13 in two younger siblings performed according to the method of Gerritsen et al. was unmeasurable (<3%, reference range 30 – 120%). The ADAMTS 13 inhibitor was undetectable. Both patients are treated with fresh frozen plasma (FFP) infusions every 4 weeks. Precise diagnosis is very important for proper treatment. Only regular FFP infusions as ADAMTS 13 supplementation can assure normal health condition of children with familial TTP.

Two generations with familial thrombotic thrombocytopenic purpura

Thrombotic thrombocytopenic purpura (TTP) is a rare multi-system disease characterised by the pentad of microangiopathic haemolytic anaemia, thrombocytopenia, renal dysfunction, fever and neurologic changes. A hereditary form of recurrent familial TTP has been described, which usually presents in adolescence or early adulthood and can lead to recurrent or chronic relapsing TTP. Genetic analyses of patients with familial TTP have linked the disease to chromosome 9q34, and an increased incidence is seen in people with HLA-B40 group antigens. We describe here an 11-year-old Egyptian girl with no significant past medical history who presented with new onset of bruising, petechial rash, fatigue and fevers and was diagnosed with familial TTP. Further testing revealed that both the patient and her father had the HLA-B40 group antigen and also had ADAMTS-13 von Willebrand factor-cleaving protease deficiency as well as factor-H deficiency.

Complement Factor H Mutation in Familial Thrombotic Thrombocytopenic Purpura with ADAMTS13 Deficiency and Renal Involvement

Thrombotic thrombocytopenic purpura is a rare disorder of small vessels that is associated with deficiency of the von Willebrand factor-cleaving protease ADAMTS13, which favors platelet adhesion and aggregation in the microcirculation. The disease manifests mainly with central nervous system symptoms, but cases of renal insufficiency have been reported. Presented are findings of the genetic basis of phenotype heterogeneity in thrombotic thrombocytopenic purpura in two sisters within one family. The patients had ADAMTS13 deficiency as a result of two heterozygous mutations (causing V88M and G1239V changes). In addition, a heterozygous mutation (causing an S890I change) in factor H of complement was found in the patient who developed chronic renal failure but not in her sister, who presented with exclusive neurologic symptoms.

Additional Environmental and/or Genetic Factors Are Required to Trigger TTP in ADAMTS13-Deficient Mice.

Thrombotic Thrombocytopenic Purpura (TTP) is a life threatening systemic illness characterized by the formation of platelet-rich thrombi in the microcirculation and the clinical pentad of fever, hemolytic anemia, thrombocytopenia, neurological symptoms, and renal dysfunction. TTP is associated with ultra-large von Willebrand Factor multimers (UL-VWF) in the circulation due to deficiency of the ADAMTS13 metalloprotease. ADAMTS13 gene mutations account for most if not all cases of familial TTP, and autoantibodies to ADAMTS13 underlie most cases of acquired TTP. To further explore the pathogenesis of TTP in vivo, ADAMTS13 deficient mice were generated by gene targeting to remove exons 1–6 which encode most of the protease domain of ADAMTS13. Although the resulting homozygous null mice (Adamts13−/−) have lost all specific VWF-cleaving protease activity (< 1% of control), embryonic development is normal, and the null mice are born at the expected Mendelian frequency. Analysis of baseline hematologic parameters and peripheral blood smears revealed no difference between Adamts13−/− mice and wild-type littermates, with no evidence for thrombocytopenia or microangiopathic hemolytic anemia. Pathologic survey of multiple tissues revealed only normal histology and no evidence for platelet or VWF-rich thrombi in the vasculature. Despite the absence of VWF-cleaving protease activity, plasma from wild-type and ADAMTS13-deficient mice exhibited identical VWF multimer size distributions. However, VWF multimers from both wild-type and Adamts13−/− mice were observed to be considerably larger than those from normal human plasma, and equivalent in size to UL-VWF seen in plasma from familial TTP patients. Challenge of Adamts13−/− mice by injection with endotoxin, and genetic crosses to mice with markedly elevated VWF levels (CASA/Rk), failed to induce findings consistent with TTP. However, treatment with verotoxin-2 (a bacterial endothelial toxin important in the pathogenesis of the hemolytic uremic syndrome), caused thrombocytopenia in 6 of 11 Adamts13−/− mice (vs. 3 of 11 wild-type controls, p < 0.07) and mortality at 6 days in 9 of 11 Adamts13−/− mice (vs. 6 of 11 controls, p < 0.02). Examination of peripheral blood from one of the Adamts13−/− mice at 8 days following verotoxin administration demonstrated marked microangiopathic changes. In conclusion, mice with targeted disruption of the Adamts13 gene do not develop TTP spontaneously, suggesting the requirement for additional environmental triggers or genetic modifiers. Though some humans with congenital ADAMTS13 deficiency have been reported to remain asymptomatic for many years, the increased size of the baseline VWF multimer distribution in mice may indicate a higher threshold for VWF-ADAMTS13 interaction which may be protective for TTP. Our results also suggest that microbial-derived toxins, or other sources of endothelial injury, may be one of the key environmental triggers responsible for the lack of spontaneous TTP findings in the ADAMTS13-deficient mice, and possibly for the intermittent symptoms seen in humans.

Measurement of von Willebrand factor cleaving protease (ADAMTS‐13): results of an international collaborative study involving 11 methods testing the same set of coded plasmas

ADAMTS-13 is a von Willebrand factor (VFW)-cleaving protease. Its congenital or acquired deficiency is associated with thrombotic thrombocytopenic purpura (TTP) and more rarely with the hemolytic uremic syndrome. We report on a survey evaluating 11 methods for ADAMTS-13 measurement performed in different labs. Two plasmas, one normal and one from a patient with familial TTP, were mixed at the co-ordinating center to prepare 6 plasmas with 0%, 10%, 20%, 40%, 80% and 100% ADAMTS-13 levels. Each plasma was aliquoted and assembled into sets of 60 (coded from 1 to 60), each containing 10 copies of the original 6 plasmas. Plasmas were frozen and shipped in dry ice to 10 labs with a common frozen reference plasma. Laboratories were asked to measure ADAMTS-13 with their methods. Results were sent to the coordinating center for statistical analysis. Of the 10 methods performed under static conditions 9 were quantitative and one was semiquantitative. One method performed under flow conditions evaluated the extent of cleavage of endothelial cell-derived ultralarge VWF string-like structures and expressed results as deficient, normal, or borderline. Linearity (expected-vs-observed levels), assessed as the squared correlation coefficient, ranged from 0.98 to 0.39. Reproducibility, expressed as the coefficient of variation for repeated measurements, ranged from < 10% to 83%. The majority of methods were able to discriminate between different ADAMTS-13 levels. The majority were able to detect the plasma with 0% level and some of them to discriminate between 0% and 10%. Overall the best performance was observed for three methods measuring cleaved VWF by ristocetin cofactor, collagen binding, and immunoblotting of degraded multimers of VWF substrate, respectively. The poor interlaboratory agreement of results was hardly affected by the use of the common standard. The method performed under flow conditions identified the plasmas with 0%, 10%, 20% and 40% activity as deficient in 7, 5, 1 and 3 of the 10 replicate measurements. The plasmas with 80% and 100% were identified as normal in all of the 10 replicate measurements. The survey shows varied performance, but supports an optimistic view about the reliability of current methods for ADAMTS-13.

Proteolytic cleavage of von Willebrand factor by ADAMTS‐13 prevents uninvited clumping of blood platelets

Proteolytic cleavage of von Willebrand factor by ADAMTS‐13 prevents uninvited clumping of blood platelets

Von Willebrand factor, ADAMTS-13, and thrombotic thrombocytopenic purpura

Thrombotic thrombocytopenic purpura (TTP) is a severe, occlusive, microvascular “thrombotic microangiopathy” characterized by systemic platelet aggregation, organ ischemia, profound thrombocytopenia, and erythrocyte fragmentation. Failure to degrade “unusually large” (UL) von Willebrand factor (VWF) multimers as they are secreted from endothelial cells probably causes most cases of familial TTP, acquired idiopathic TTP, thienopyridine-related TTP, and pregnancy-associated TTP. The emphasis in this review is the pathophysiology of familial and acquired idiopathic TTP. In each of these entities, there is a severe defect in the function of a plasma enzyme, VWF-cleaving metalloprotease (ADAMTS-13), that normally cleaves hyper-reactive ULVWF multimers into smaller and less adhesive VWF forms. In familial TTP, mutations in the ADAMTS13 gene cause absent or severely reduced plasma VWF-cleaving metalloprotease activity. Acquired idiopathic TTP, in contrast, is the result in many patients of the production of autoantibodies that inhibit the function of ADAMTS-13. Established, evolving, and some of the unresolved issues in TTP pathophysiology will be summarized.

Mutation analysis and clinical implications of von Willebrand factor–cleaving protease deficiency

The pentad of thrombocytopenia, hemolytic anemia, mild renal dysfunction, neurologic signs, and fever, classically characterizes the syndrome of thrombotic thrombocytopenic purpura (TTP). TTP usually occurs in adults as an acquired form but a congenital form in children has also been described. In the latter case, the initial presentation is often with neonatal jaundice and thrombocytopenia. The disorder may subsequently take a relapsing course. Deficiency of a recently identified novel metalloprotease, the von Willebrand factor (vWF)-cleaving protease, originating from mutations in the ADAMTS13 gene plays a major role in the development of TTP. Blood for DNA analysis was collected from six unrelated TTP families, consisting of nine patients from four different countries, and was screened for mutations in the ADAMTS13 gene. This gene spans 29 exons encompassing approximately 37 kb. Conventional techniques of DNA extraction, polymerase chain reaction (PCR), and direct cycle sequencing were used. Eight novel ADAMTS13 mutations are presented. Half of the total number of mutant ADAMTS13 alleles are amino acid substitutions. The disease-causing mutations are spread over the gene. The pathogenicity of the individual mutations is based upon their predicted effect on the ADAMTS13 protein and segregation in family members. Although most of the patients (seven out of nine) had symptoms during the neonatal period, they were in a remarkably good condition. Only one of the nine patients had a decreased glomerular filtration rate (GFR) with proteinuria and hematuria. Another patient had epileptic seizures. We confirm that deficiency of ADAMTS13 is a molecular mechanism responsible for familial TTP. An early diagnosis allows prophylactic treatment with fresh plasma infusions.

Remission of thrombotic thrombocytopenic purpura in a patient with compound heterozygous deficiency of von Willebrand factor‐cleaving protease by infusion of solvent/detergent plasma

Plasma exchange or plasma infusion is considered to be the therapy of choice in patients with thrombotic thrombocytopenic purpura (TTP) who are deficient in von Willebrand factor‐cleaving protease (VWF‐CP). Recently, mutations in the ADAMTS13 gene were identified as being responsible for VWF‐CP deficiency in patients with familial TTP (VWF‐CP deficiency in the absence of an inhibitor). Here we report on a girl who presented with recurrent thrombocytopenia and anaemia since birth, developing the full pentad of characteristic TTP at the age of 16y. Congenital TTP was confirmed on the basis of severe VWF‐CP deficiency in the absence of an acquired inhibitor. The patient was found to be compound heterozygous for two hitherto undescribed mutations in the ADAMTS13 gene: a truncating frame shift mutation, 4143insA in exon 29, and the nonsense mutation 3100A &gt; T in exon 24 (R1034X). After infusion of solvent/detergent plasma, the patient went into remission and remained asymptomatic under regular plasma therapy at 2‐wk intervals for over two years. Conclusion: TTP in childhood may be mild and oligosymptomatic. Determination of VWF‐CP activity is helpful in the differential diagnosis of thrombocytopenia.

Von Willebrand factor cleaving protease (ADAMTS13) is deficient in recurrent and familial thrombotic thrombocytopenic purpura and hemolytic uremic syndrome

AbstractWhether measurement of ADAMTS13 activity may enable physicians to distinguish thrombotic thrombocytopenic purpura (TTP) from hemolytic uremic syndrome (HUS) is still a controversial issue. Our aim was to clarify whether patients with normal or deficient ADAMTS13 activity could be distinguished in terms of disease manifestations and multimeric patterns of plasma von Willebrand factor (VWF). ADAMTS13 activity, VWF antigen, and multimeric pattern were evaluated in patients with recurrent and familial TTP (n = 20) and HUS (n = 29). Results of the collagen-binding assay of ADAMTS13 activity were confirmed in selected samples by testing the capacity of plasma to cleave recombinant VWF A1-A2-A3. Most patients with TTP had complete or partial deficiency of ADAMTS13 activity during the acute phase, and in some the defect persisted at remission. However, complete ADAMTS13 deficiency was also found in 5 of 9 patients with HUS during the acute phase and in 5 patients during remission. HUS patients with ADAMTS13 deficiency could not be distinguished clinically from those with normal ADAMTS13. In a subgroup of patients with TTP or HUS, the ADAMTS13 defect was inherited, as documented by half-normal levels of ADAMTS13 in their asymptomatic parents, consistent with the heterozygous carrier state. In patients with TTP and HUS there was indirect evidence of increased VWF fragmentation, and this occurred also in patients with ADAMTS13 deficiency. In conclusion, deficient ADAMTS13 activity does not distinguish TTP from HUS, at least in the recurrent and familial forms, and it is not the only determinant of VWF abnormalities in these conditions.

Assays of von Willebrand factor-cleaving protease: a test for diagnosis of familial and acquired thrombotic thrombocytopenic purpura.

Endothelial cells secrete von Willebrand factor (vWF) multimers that are larger than those found in the circulating plasma. These very large multimeric forms of vWF, capable of spontaneously binding to and agglutinating the blood platelets under conditions of high fluid shear rate, are degraded by a specific metalloprotease cleaving the peptide bond 842Tyr-843Met of the vWF subunit. The vWF-cleaving protease was found to be deficient in patients with familial thrombotic thrombocytopenic purpura (TTP). The acute events in these patients can be successfully treated and prophylactically prevented by repletion of the missing protease using fresh frozen plasma (FFP). In another, apparently more common, form of TTP, the protease deficiency is due to inhibiting circulating antibodies directed against the vWF-cleaving protease. Therapy of these patients should include immunosuppressive treatment in addition to plasma exchange and replacement with FFP. Normal activity of vWF-cleaving protease was established in patients with a clinically similar disorder: hemolytic-uremic syndrome (HUS). The level of vWF-cleaving protease activity is thus a laboratory parameter that provides important information for the differential diagnosis and treatment of patients with TTP/HUS. Several assays of vWF-cleaving protease have been described and are summarized here.

Laparoscopic splenectomy in patients with refractory or relapsing thrombotic thrombocytopenic purpura.

Thrombotic thrombocytopenic purpura (TTP) is a rare and serious hematological disease. First-line therapy is plasma exchange, often used in combination with corticosteroids, vincristine, aspirin, and dipyridamole. The role of splenectomy for patients resistant to or dependent on plasma therapy and for the prevention of TTP relapses is not yet determined. Laparoscopic splenectomy (LS) is effective and safe for the treatment of the chronic relapsing form of TTP. We performed LS in 8 patients with refractory or relapsing TTP. The operative as well as the early and late postoperative course and complications were recorded. The mean duration of LS was 70 minutes (range, 35-180 minutes). There were no serious bleeding complications during or after surgery. Convalescence was rapid, and the mean hospital stay was 2.5 days (range, 1-9 days). Patients were followed up for a mean of 32 months (range, 19-54 months). Seven patients are in remission with no relapse of TTP. One patient with familial TTP had multiple relapses before and after surgery. Laparoscopic splenectomy for refractory or relapsing TTP is safe and associated with low morbidity and fast recovery. It is effective in the long-term prevention of TTP relapses in most patients, and it should probably be considered early in the course of chronic, relapsing TTP.