Essentials
An international collaboration provides a consensus for clinical definitions.
This concerns thrombotic microangiopathies and thrombotic thrombocytopenic purpura (TTP).
The consensus ...defines diagnosis, disease monitoring and response to treatment.
Requirements for ADAMTS‐13 are given.
Summary
Background
Thrombotic thrombocytopenic purpura (TTP) and hemolytic–uremic syndrome (HUS) are two important acute conditions to diagnose. Thrombotic microangiopathy (TMA) is a broad pathophysiologic process that leads to microangiopathic hemolytic anemia and thrombocytopenia, and involves capillary and small‐vessel platelet aggregates. The most common cause is disseminated intravascular coagulation, which may be differentiated by abnormal coagulation. Clinically, a number of conditions present with microangiopathic hemolytic anemia and thrombocytopenia, including cancer, infection, transplantation, drug use, autoimmune disease, and pre‐eclampsia and hemolysis, elevated liver enzymes and low platelet count syndrome in pregnancy. Despite overlapping clinical presentations, TTP and HUS have distinct pathophysiologies and treatment pathways.
Objectives
To present a consensus document from an International Working Group on TTP and associated thrombotic microangiopathies (TMAs).
Methods
The International Working Group has proposed definitions and terminology based on published information and consensus‐based recommendations.
Conclusion
The consensus aims to aid clinical decisions, but also future studies and trials, utilizing standardized definitions. It presents a classification of the causes of TMA, and criteria for clinical response, remission and relapse of congenital and immune‐mediated TTP.
Among patients with thrombotic thrombocytopenic purpura, the addition of caplacizumab, an anti–von Willebrand factor humanized, bivalent variable-domain-only immunoglobulin fragment, to daily plasma ...exchange resulted in faster platelet recovery, fewer TTP-related deaths, and fewer recurrences and thromboembolic events.
Summary
Thrombotic microangiopathies are rare disorders characterized by the concomitant occurrence of severe thrombocytopenia, microangiopathic hemolytic anemia, and a variable degree of ischemic ...end‐organ damage. The latter particularly affects the brain, the heart, and the kidneys. The primary forms, thrombotic thrombocytopenic purpura (TTP) and hemolytic uremic syndrome (HUS), although their clinical presentations often overlap, have distinctive pathophysiologies. TTP is the consequence of a severe ADAMTS‐13 deficiency, either immune‐mediated as a result of circulating autoantibodies, or caused by mutations in ADAMTS‐13. HUS develops following an infection with Shiga‐toxin producing bacteria, or as the result of excessive activation of the alternative pathway of the complement system because of mutations in genes encoding complement system proteins.
Essentials
Acquired thrombotic thrombocytopenic purpura (aTTP) is linked with significant morbidity/mortality.
Caplacizumab's effect on major thromboembolic (TE) events, exacerbations and death was ...studied.
Fewer caplacizumab‐treated patients had a major TE event, an exacerbation, or died versus placebo.
Caplacizumab has the potential to reduce the acute morbidity and mortality associated with aTTP.
Summary
Background
Acquired thrombotic thrombocytopenic purpura (aTTP) is a life‐threatening autoimmune thrombotic microangiopathy. In spite of treatment with plasma exchange and immunosuppression, patients remain at risk for thrombotic complications, exacerbations, and death. In the phase II TITAN study, treatment with caplacizumab, an anti‐von Willebrand factor Nanobody® was shown to reduce the time to confirmed platelet count normalization and exacerbations during treatment.
Objective
The clinical benefit of caplacizumab was further investigated in a post hoc analysis of the incidence of major thromboembolic events and exacerbations during the study drug treatment period and thrombotic thrombocytopenic purpura‐related death during the study.
Methods
The Standardized Medical Dictionary for Regulatory Activities (MedDRA) Query (SMQ) for ‘embolic and thrombotic events’ was run to investigate the occurrence of major thromboembolic events and exacerbations in the safety population of the TITAN study, which consisted of 72 patients, of whom 35 received caplacizumab and 37 received placebo.
Results
Four events (one pulmonary embolism and three aTTP exacerbations) were reported in four patients in the caplacizumab group, and 20 such events were reported in 14 patients in the placebo group (two acute myocardial infarctions, one ischemic stroke, one hemorrhagic stroke, one pulmonary embolism, one deep vein thrombosis, one venous thrombosis, and 13 aTTP exacerbations). Two of the placebo‐treated patients died from aTTP during the study.
Conclusion
In total, 11.4% of caplacizumab‐treated patients and 43.2% of placebo‐treated patients experienced one or more major thromboembolic events, experienced an exacerbation, or died. This analysis shows the potential for caplacizumab to reduce the risk of major thromboembolic morbidities and mortality associated with aTTP.
Background: ADAMTS13‐neutralizing IgG autoantibodies are the major cause of acquired thrombotic thrombocytopenic purpura (TTP). Objective: To analyze the IgG subclass distribution of anti‐ADAMTS13 ...antibodies and a potential relationship between subclass distribution and disease prognosis. Methodology: An enzyme‐linked immunosorbent assay‐based method was used to quantify the relative amounts of IgG subclasses of anti‐ADAMTS13 antibodies in acquired TTP plasma. Results: IgG4 (52/58, 90%) was the most prevalent IgG subclass in patients with acquired TTP, followed by IgG1 (52%), IgG2 (50%), and IgG3 (33%). IgG4 was found either alone (17/52) or with other IgG subclasses (35/52). IgG4 was not detected in 10% of the patients. There was an inverse correlation between the frequency and abundance of IgG4 and IgG1 antibodies (P < 0.01). Patients with high IgG4 levels and undetectable IgG1 are more prone to relapse than patients with low IgG4 levels and detectable IgG1. Conclusions: All IgG subclasses of anti‐ADAMTS13 antibodies were detected in patients with acquired TTP, with IgG4, followed by IgG1, antibodies dominating the anti‐ADAMTS13 immune response. Levels of IgG4 could be useful for the identification of patients at risk of disease recurrence.
Summary
Background
Acute thrombotic microangiopathies (TMAs) are characterized by excessive microvascular thrombosis and are associated with markers of neutrophil extracellular traps (NETs) in ...plasma. NETs are composed of DNA fibers and promote thrombus formation through the activation of platelets and clotting factors.
Objective
The efficient removal of NETs may be required to prevent excessive thrombosis such as in TMAs. To test this hypothesis, we investigated whether TMAs are associated with a defect in the degradation of NETs.
Methods and Results
We show that NETs generated in vitro were efficiently degraded by plasma from healthy donors. However, NETs remained stable after exposure to plasma from TMA patients. The inability to degrade NETs was linked to a reduced DNase activity in TMA plasma. Plasma DNase1 was required for efficient NET degradation and TMA plasma showed decreased levels of this enzyme. Supplementation of TMA plasma with recombinant human DNase1 restored NET‐degradation activity.
Conclusions
Our data indicate that DNase1‐mediated degradation of NETs is impaired in patients with TMAs. The role of plasma DNases in thrombosis is, as of yet, poorly understood. Reduced plasma DNase1 activity may cause the persistence of pro‐thrombotic NETs and thus promote microvascular thrombosis in TMA patients.
Essentials
The population prevalence of hereditary thrombotic thrombocytopenic purpura (TTP) is unknown.
We studied the prevalence of hereditary TTP and population frequencies of two ADAMTS‐13 ...mutations.
A high frequency of hereditary TTP related to ADAMTS‐13 mutation c.4143_4144dupA was found.
Vicinity of ABO blood group and ADAMTS‐13 loci may facilitate screening of ADAMTS‐13 mutations.
Summary
Background
Hereditary thrombotic thrombocytopenic purpura (TTP) caused by ADAMTS‐13 mutations is a rare, but serious condition. The prevalence is unknown, but it seems to be high in Norway.
Objectives
To identify all patients with hereditary TTP in central Norway and to investigate the prevalence of hereditary TTP and the population frequencies of two common ADAMTS‐13 mutations.
Patients/Methods
Patients were identified in a cross‐sectional study within the Central Norway Health Region by means of three different search strategies. Frequencies of ADAMTS‐13 mutations, c.4143_4144dupA and c.3178 C>T (p.R1060W), were investigated in a population‐based cohort (500 alleles) and in healthy blood donors (2104 alleles) by taking advantage of the close neighborhood of the ADAMTS‐13 and ABO blood group gene loci. The observed prevalence of hereditary TTP was compared with the rates of ADAMTS‐13 mutation carriers in different geographical regions.
Results
We identified 11 families with hereditary TTP in central Norway during the 10‐year study period. The prevalence of hereditary TTP in central Norway was 16.7 × 10−6 persons. The most prevalent mutation was c.4143_4144dupA, accounting for two‐thirds of disease causing alleles among patients and having an allelic frequency of 0.33% in the central, 0.10% in the western, and 0.04% in the southeastern Norwegian population. The allelic frequency of c.3178 C>T (p.R1060W) in the population was even higher (0.3–1%), but this mutation was infrequent among patients, with no homozygous cases.
Conclusions
We found a high prevalence of hereditary TTP in central Norway and an apparently different penetrance of ADAMTS‐13 mutations.
Background: Severe deficiency of the von Willebrand factor (VWF)‐cleaving protease ADAMTS13 as observed in acquired thrombotic thrombocytopenic purpura (TTP) is caused by inhibitory and ...non‐inhibitory autoantibodies directed against the protease. Current treatment with plasma exchange is considered to remove circulating antibodies and to concurrently replenish the deficient enzyme. Objectives: To explore the use of recombinant ADAMTS13 (rADAMTS13) as a potential therapeutic agent in acquired TTP, we investigated its efficacy in normalizing VWF‐cleaving activity in the presence of ADAMTS13 inhibitors. Methods: Thirty‐six plasma samples from TTP patients were adjusted to predefined inhibitor titers, and recovery of ADAMTS13 activity was analyzed following supplementation with rADAMTS13. Results: We showed a linear relation between the inhibitor titer measured and effective rADAMTS13 concentration necessary for reconstitution of VWF‐cleaving activity in the presence of neutralizing autoantibodies. Conclusions: Our results support the further investigation of the potential therapeutic applicability of rADAMTS13 as an adjunctive therapy in acquired TTP.
Background: Insufficient control of von Willebrand factor (VWF) multimer size as a result of severely deficient ADAMTS‐13 activity results in thrombotic thrombocytopenic purpura associated with ...microvascluar thrombosis and platelet consumption, features not seldom seen in severe sepsis and septic shock. Methods: ADAMTS‐13 activity and VWF parameters of 40 patients with severe sepsis or septic shock were compared with those of 40 healthy controls of the same age and gender and correlated with clinical findings and sepsis outcome. Results: ADAMTS‐13 activity was significantly lower in patients than in healthy controls median 60% (range 27–160%) vs. 110% (range 63–200%); P < 0.001. VWF parameters behaved reciprocally and both VWF ristocetin cofactor activity (RCo) and VWF antigen (VWF:Ag) were significantly (P < 0.001) higher in patients compared with controls. Neither ADAMTS‐13 activity nor VWF parameters correlated with disease severity, organ dysfunction or outcome. However, a contribution of acute endothelial dysfunction to renal impairment in sepsis is suggested by the significantly higher VWF propeptide and soluble thrombomodulin levels in patients with increased creatinine values as well as by their strong positive correlations (creatinine and VWF propeptide rs = 0.484, P < 0.001; creatinine and soluble thrombomodulin rs = 0.596, P < 0.001). Conclusions: VWF parameters are reciprocally correlated with ADAMTS‐13 activity in severe sepsis and septic shock but have no prognostic value regarding outcome.
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