scholarly journals THROMBOTIC THROMBOCYTOPENIC PURPURA (TTP) AND MODERN APPROACH TO ITS INVESTIGATION AND TREATMENT

2019 ◽  
pp. 12-13
Author(s):  
K. Ukleba ◽  
L. Gvetadze
Keyword(s):  
Thrombotic Thrombocytopenic Purpura ◽  
Severe Thrombocytopenia ◽  
Thrombocytopenic Purpura ◽  
Modern Approach ◽  
Severe Deficiency ◽  
Life Threatening ◽  
Adamts13 Deficiency ◽  
Von Willebrand ◽  
Willebrand Factor

Thrombotic thrombocytopenic purpura (TTP) is a rare and life-threatening thrombotic microangiopathy characterized by microangiopathic hemolytic anemia, severe thrombocytopenia, and organ ischemia linked to disseminated microvascular platelet rich-thrombi. TTP is specifically related to a severe deficiency in ADAMTS13 (a disintegrin and metalloprotease with thrombospondin type 1 repeats, member 13), the specific von Willebrand factor-cleaving protease. ADAMTS13 deficiency is most frequently acquired via ADAMTS13 autoantibodies, but rarely, it is inherited via mutations of the ADAMTS13 gane. The first acute episode of TTP usually occurs during adulthood, with a predominant anti – ADAMTS13 autoimmune etiology. In rare cases, however, TTP begins as soon as childhood, with frequent inherited forms. TTP is 2 – fold more frequent in women, and its outcome is characterized by a relapsing tendency.

Epitope mapping of ADAMTS13 autoantibodies in acquired thrombotic thrombocytopenic purpura

Blood ◽  
2004 ◽  
Vol 103 (12) ◽  
pp. 4514-4519 ◽  
Author(s):  
Christoph Klaus ◽  
Barbara Plaimauer ◽  
Jan-Dirk Studt ◽  
Friedrich Dorner ◽  
Bernhard Lämmle ◽  
...  
Keyword(s):  
Thrombotic Thrombocytopenic Purpura ◽  
Thrombocytopenic Purpura ◽  
Severe Deficiency ◽  
Adamts13 Deficiency ◽  
Multiple Domains ◽  
Von Willebrand ◽  
Recombinant Fragments ◽  
Willebrand Factor

Abstract Severe deficiency of the von Willebrand factor (VWF)-cleaving protease ADAMTS13 can lead to thrombotic thrombocytopenic purpura (TTP), a disease associated with the widespread formation of platelet-rich thrombi in many organs. Autoantibodies that inactivate ADAMTS13 are the most frequent cause of acquired TTP. Little is known about epitope specificity and reactivity of anti-ADAMTS13 antibodies. In this study, a series of ADAMTS13 domains were expressed in Escherichia coli, and the reactivity of purified recombinant fragments with anti-ADAMTS13 auto-antibodies from 25 patients with severe ADAMTS13 deficiency was evaluated in vitro. All TTP plasmas contained antibodies directed against the cysteine-rich spacer (cys-rich/spacer) domain of ADAMTS13. In the plasma of 3 patients, antibodies were detected that reacted exclusively with the cys-rich/spacer domain, underscoring the importance of this region for functional activity of ADAMTS13. In 64% of the plasmas, antibodies reacted with the 2 CUB domains, and in 56% they reacted with the isolated first thrombospondin type 1 (TSP-1) repeat and with the compound fragment consisting of the catalytic, the disintegrin-like, and the TSP1-1 domain. Less frequently, in 28% of the plasmas, antibodies reacted with the TSP1 repeats 2 to 8. Unexpectedly, antibodies reacted with the propeptide region in 20% of the plasmas. In conclusion, this study shows that even though anti-ADAMTS13 autoantibodies react with multiple domains of the protease, the cys-rich/spacer domain is consistently involved in antibody reactivity. (Blood. 2004;103:4514-4519)

scholarly journals Pathophysiology of thrombotic thrombocytopenic purpura

Blood ◽  
2017 ◽  
Vol 130 (10) ◽  
pp. 1181-1188 ◽  
Author(s):  
J. Evan Sadler
Keyword(s):  
Thrombotic Thrombocytopenic Purpura ◽  
Tissue Injury ◽  
Preventive Therapy ◽  
Neurological Deficits ◽  
Autoantibody Production ◽  
Thrombocytopenic Purpura ◽  
Adamts13 Deficiency ◽  
Von Willebrand ◽  
Willebrand Factor

Abstract The discovery of a disintegrin-like and metalloproteinase with thrombospondin type 1 motif, member 13 (ADAMTS13) revolutionized our approach to thrombotic thrombocytopenic purpura (TTP). Inherited or acquired ADAMTS13 deficiency allows the unrestrained growth of microthrombi that are composed of von Willebrand factor and platelets, which account for the thrombocytopenia, hemolytic anemia, schistocytes, and tissue injury that characterize TTP. Most patients with acquired TTP respond to a combination of plasma exchange and rituximab, but some die or acquire irreversible neurological deficits before they can respond, and relapses can occur unpredictably. However, knowledge of the pathophysiology of TTP has inspired new ways to prevent early deaths by targeting autoantibody production, replenishing ADAMTS13, and blocking microvascular thrombosis despite persistent ADAMTS13 deficiency. In addition, monitoring ADAMTS13 has the potential to identify patients who are at risk of relapse in time for preventive therapy.

FRETS-VWF73 rather than CBA assay reflects ADAMTS13 proteolytic activity in acquired thrombotic thrombocytopenic purpura patients

2014 ◽  
Vol 112 (08) ◽  
pp. 297-303 ◽  
Author(s):  
Ilaria Mancini ◽  
Carla Valsecchi ◽  
Luca Lotta ◽  
Louis Deforche ◽  
Silvia Pontiggia ◽  
...  
Keyword(s):  
Thrombotic Thrombocytopenic Purpura ◽  
Proteolytic Activity ◽  
Binding Activity ◽  
Adamts13 Activity ◽  
Flow Conditions ◽  
Thrombocytopenic Purpura ◽  
Severe Deficiency ◽  
Adamts13 Deficiency ◽  
Von Willebrand ◽  
Willebrand Factor

SummaryCollagen-binding activity (CBA) and FRETS-VWF73 assays are widely adopted methods for the measurement of the plasmatic activity of ADAMTS13, the von Willebrand factor (VWF) cleaving-protease. Accurately assessing the severe deficiency of ADAMTS13 is important in the management of thrombotic thrombocytopenic purpura (TTP). However, non-concordant results between the two assays have been reported in a small but relevant percentage of TTP cases. We investigated whether CBA or FRETS-VWF73 assay reflects ADAMTS13 proteolytic activity in acquired TTP patients with non-concordant measurements. Twenty plasma samples with non-concordant ADAMTS13 activity results, <10% using FRETS-VWF73 and ≥20% using CBA, and 11 samples with concordant results, <10% using either FRETS-VWF73 and CBA assays, were analysed. FRETS-VWF73 was performed in the presence of 1.5 M urea. ADAMTS13 activities were also measured under flow conditions and the VWF multimer pattern was defined in order to verify the presence of ultra-large VWF due to ADAMTS13 deficiency. In FRETS-VWF73 assay with 1.5 M urea, ADAMTS13 activity significantly increased in roughly 50% of the samples with non-concordant results, whereas it remained undetectable in all samples with concordant measurements. Under flow conditions, all tested samples showed reduced ADAMTS13 activity. Finally, samples with non-concordant results showed a ratio of high molecular weight VWF multimers higher than normal. Our results support the use of FRETS-VWF73 over CBA assay for the assessment of ADAMTS13 severe deficiency and indicate urea as one cause of the observed differences.

scholarly journals A case of severe ADAMTS 13 deficiency presenting as thrombotic thrombocytopenic purpura in pregnancy

2012 ◽  
Vol 65 (9-10) ◽  
pp. 436-439 ◽  
Author(s):  
Marinos Nikolaou ◽  
Marina Karakantza ◽  
George Adonakis ◽  
George Theodorou ◽  
Nikolaos Zoumbos ◽  
...  
Keyword(s):  
Thrombotic Thrombocytopenic Purpura ◽  
Prophylactic Treatment ◽  
Thrombocytopenic Purpura ◽  
Treatment And Prevention ◽  
Severe Deficiency ◽  
History Of ◽  
Adamts13 Deficiency ◽  
Von Willebrand ◽  
Willebrand Factor ◽  
Plasma Infusions

Introduction. Thrombotic thrombocytopenic purpura is a rare lifethreatening disorder characterized by thrombocytopenia and microangiopathic hemolytic anemia. It is caused by the absent or severe deficiency of the von Willebrand Factor-cleaving protease named ADAMTS13. Pregnancy is a well recognized factor precipitating the appearance of the disease both in women that had reduced levels of ADAMTS13 activity prior to gestation and in those with other inherited or acquired thrombophilic syndromes. Case Report. We report a 25-year old woman with severe ADAMTS13 deficiency presented early in her 1st pregnancy and relapsed in two subsequent gestations. This presentation is uncommon for thrombotic thrombocytopenic purpura is associated with pregnancy (ADAMTS13 deficiency <5%, without an inhibitor). In the first pregnancy she started with daily plasma exchange 1.5xvolume, corticosteroids and IV immunoglobulin and finally entered remission after 23 sessions and termination of pregnancy. In the second pregnancy she did not receive prophylactic treatment and relapsed in the 3rd trimester. Prophylactic treatment during the third pregnancy with plasma infusions proved also ineffective to prevent relapse. Discussion. Many issues regarding treatment and prevention of thrombotic thrombocytopenic purpura relapses in subsequent pregnancies are unclear. Proposed guidelines recommend that the same treatment should be performed on pregnant and non pregnant patients without modification of plasma replacement dose according to ADAMTS13 levels. In addition, many authors suggest that pregnant patients with history of thrombotic thrombocytopenic purpura and severe deficiency of ADAMTS13 levels should received prophylactic treatment for prevention of relapses in the subsequent pregnancies. Conclusion. Severe ADAMTS 13 deficiency may present as thrombotic thrombocytopenic purpura of pregnancy. Pregnant women with thrombotic thrombocytopenic purpura and especially with severe deficiency of ADAMTS13 levels require specific consideration regarding treatment and prophylaxis in subsequent pregnancies.

scholarly journals Unexpected frequency of Upshaw-Schulman syndrome in pregnancy-onset thrombotic thrombocytopenic purpura

Blood ◽  
2012 ◽  
Vol 119 (24) ◽  
pp. 5888-5897 ◽  
Author(s):  
Marie Moatti-Cohen ◽  
Céline Garrec ◽  
Martine Wolf ◽  
Pierre Boisseau ◽  
Lionel Galicier ◽  
...  
Keyword(s):  
Thrombotic Thrombocytopenic Purpura ◽  
National Registry ◽  
Cross Sectional ◽  
Thrombocytopenic Purpura ◽  
Severe Deficiency ◽  
Specific Subgroup ◽  
Life Threatening ◽  
Adamts13 Deficiency ◽  
Sectional Analysis

Abstract Pregnancy may be complicated by a rare but life-threatening disease called thrombotic thrombocytopenic purpura (TTP). Most cases of TTP are due to an acquired autoimmune or hereditary (Upshaw-Schulman syndrome [USS]) severe deficiency of a disintegrin and metalloprotease with thrombospondin type 1 repeats, member 13 (ADAMTS13). In the present study, we performed a cross-sectional analysis of the national registry of the French Reference Center for Thrombotic Microangiopathies from 2000-2010 to identify all women who were pregnant at their initial TTP presentation. Among 592 adulthood-onset TTP patients with a severe ADAMTS13 deficiency, 42 patients with a pregnancy-onset TTP were included. Surprisingly, the proportion of USS patients (n = 10 of 42 patients [24%]; confidence interval, 13%-39%) with pregnancy-onset TTP was much higher than that in adulthood-onset TTP in general (less than 5%) and was mostly related to a cluster of ADAMTS13 variants. In the present study, subsequent pregnancies in USS patients not given prophylaxis were associated with very high TTP relapse and abortion rates, whereas prophylactic plasmatherapy was beneficial for both the mother and the baby. Pregnancy-onset TTP defines a specific subgroup of patients with a strong genetic background. This study was registered at www.clinicaltrials.gov as number NCT00426686 and at the Health Authority, French Ministry of Health, as number P051064.

TTP and ADAMTS13: When Is Testing Appropriate?

Hematology ◽  
2007 ◽  
Vol 2007 (1) ◽  
pp. 121-126 ◽  
Author(s):  
Pier Mannuccio Mannucci ◽  
Flora Peyvandi
Keyword(s):  
Platelet Adhesion ◽  
Multiorgan Failure ◽  
Microangiopathic Hemolytic Anemia ◽  
Thrombocytopenic Purpura ◽  
Life Threatening ◽  
Adamts13 Deficiency ◽  
A Disintegrin And Metalloproteinase ◽  
Von Willebrand ◽  
Willebrand Factor

Abstract The last 10 years witnessed the publication of many studies on the pathophysiology of thrombotic thrombocytopenic purpura (TTP), a life-threatening disease characterized by microangiopathic hemolytic anemia, thrombocytopenia and multiorgan failure. The most important finding was the identification of a novel metalloprotease, named ADAMTS13 (a disintegrin and metalloproteinase with thrombospondin type 1 motives), that is involved in the regulation of the size of von Willebrand factor (VWF), a major modulator of platelet adhesion and aggregation in the microcirculation. Inherited or acquired deficiencies of ADAMTS13 impair VWF cleavage, leading in turn to the disseminated formation of platelet-rich thrombi in the micro-circulation and to symptoms of end-organ ischemia. By measuring ADAMTS13 in plasma, it has been clearly shown that patients with inherited TTP have severe ADAMTS13 deficiency. However, patients with acquired TTP present with clinical and laboratory heterogeneity, and there are unequivocal cases of acquired TTP with measurable plasma levels of ADAMTS13. This heterogeneity poses a challenge for understanding the pathogenesis of TTP and selecting appropriate therapies.

scholarly journals Current and Future Perspectives on ADAMTS13 and Thrombotic Thrombocytopenic Purpura

2020 ◽  
Vol 40 (03) ◽  
pp. 322-336 ◽  
Author(s):  
Elien Roose ◽  
Bérangère S. Joly
Keyword(s):  
Thrombotic Thrombocytopenic Purpura ◽  
Severe Thrombocytopenia ◽  
Thrombocytopenic Purpura ◽  
Diagnostic Assays ◽  
Severe Deficiency ◽  
Targeted Treatments ◽  
Life Threatening ◽  
Thrombospondin Type 1 Repeats

AbstractThrombotic thrombocytopenic purpura (TTP) is a rare, relapsing, and life-threatening disorder with an annual incidence of 10 cases per million people. TTP is a thrombotic microangiopathy characterized by severe thrombocytopenia, microangiopathic hemolytic anemia, and organ ischemia. The disease is caused by a severe deficiency of the enzyme ADAMTS13 (a disintegrin and metalloprotease with thrombospondin type 1 repeats, member 13), which can either be acquired, mainly by autoantibodies targeting ADAMTS13, or congenital due to mutations in the ADAMTS13 gene. Thanks to the establishment of national registries worldwide, fundamental and translational research, major advances have been made on the diagnosis, treatment, and fundamental understanding of TTP, since the description of the first TTP case almost 100 years ago. The introduction of therapeutic plasma exchange in the 1970s has significantly improved patient survival, but novel diagnostic assays, targeted treatments (rituximab, caplacizumab, recombinant ADAMTS13), and the unraveling of both ADAMTS13 function and TTP pathophysiology should help to further improve the patients' quality of life. However, differential diagnosis of TTP remains challenging and still a lot of questions remain unanswered to completely understand this rare and devastating disease.

Von Willebrand factor–cleaving protease (ADAMTS13) in thrombocytopenic disorders: a severely deficient activity is specific for thrombotic thrombocytopenic purpura

Blood ◽  
2002 ◽  
Vol 100 (2) ◽  
pp. 710-713 ◽  
Author(s):  
Valentina Bianchi ◽  
Rodolfo Robles ◽  
Lorenzo Alberio ◽  
Miha Furlan ◽  
Bernhard Lämmle
Keyword(s):  
Thrombotic Thrombocytopenic Purpura ◽  
Von Willebrand Factor ◽  
Adamts13 Activity ◽  
Thrombocytopenic Purpura ◽  
Heparin Induced Thrombocytopenia ◽  
Severe Deficiency ◽  
Uremic Syndrome ◽  
Adamts13 Deficiency ◽  
Von Willebrand ◽  
Willebrand Factor

Abstract A severe deficiency in von Willebrand factor–cleaving protease (ADAMTS13) activity (&lt; 5% that in normal plasma) has been observed in most patients with a diagnosis of thrombotic thrombocytopenic purpura (TTP) but not in those with a diagnosis of hemolytic uremic syndrome. However, ADAMTS13 deficiency has been claimed not to be specific for TTP, since it was observed in various thrombocytopenic and other conditions. We studied 68 patients with thrombocytopenia due to severe sepsis or septic shock (n = 17), heparin-induced thrombocytopenia (n = 16), idiopathic thrombocytopenic purpura (n = 10), or other hematologic (n = 15) or miscellaneous conditions (n = 10). Twelve of the 68 patients had subnormal levels of ADAMTS13 activity (≤ 30%), but none had less than 10%. Thus, the study showed that ADAMTS13 activity is decreased in a substantial proportion of patients with thrombocytopenia of various causes. A severe deficiency of ADAMTS13 (&lt; 5%), identified in more than 120 patients during 1996 to 2001 in our laboratory, is specific for a thrombotic microangiopathy commonly labeled TTP.

scholarly journals Inhibition of von Willebrand factor–platelet glycoprotein Ib interaction prevents and reverses symptoms of acute acquired thrombotic thrombocytopenic purpura in baboons

Blood ◽  
2012 ◽  
Vol 120 (17) ◽  
pp. 3611-3614 ◽  
Author(s):  
Hendrik B. Feys ◽  
Jan Roodt ◽  
Nele Vandeputte ◽  
Inge Pareyn ◽  
Harald Mottl ◽  
...  
Keyword(s):  
Thrombotic Thrombocytopenic Purpura ◽  
Von Willebrand Factor ◽  
Platelet Glycoprotein ◽  
Control Group ◽  
Severe Thrombocytopenia ◽  
Thrombocytopenic Purpura ◽  
Platelet Aggregates ◽  
New Treatment ◽  
Von Willebrand ◽  
Willebrand Factor

Abstract The pathophysiology of thrombotic thrombocytopenic purpura (TTP) can be explained by the absence of active ADAMTS13, leading to ultra-large von Willebrand factor (UL-VWF) multimers spontaneously interacting with platelets. Preventing the formation of UL-VWF–platelet aggregates therefore is an attractive new treatment strategy. Here, we demonstrate that simultaneous administration of the inhibitory anti-VWF monoclonal antibody GBR600 and the inhibitory anti-ADAMTS13 antibody 3H9 to baboons (prevention group) precluded TTP onset as severe thrombocytopenia and hemolytic anemia were absent in these animals. In addition, partial VWF inhibition was not enough to prevent thrombocytopenia, demonstrating the specificity of this therapeutic strategy. GBR600 treatment of baboons during acute TTP (treatment group) resulted in a rapid recovery of severe thrombocytopenia similar to the platelet count increases observed in TTP patients treated by plasma exchange. Baboons in the control group only injected with 3H9 developed early stages of TTP as previously described. Hence, inhibiting VWF-GPIb interactions is an effective way to prevent and treat the early symptoms of acquired TTP in baboons.

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